TDG inhibitor compound and application thereof

Abstract

The invention provides a compound for inhibiting TDG activity. Specifically, the invention provides a compound with a novel structure as shown in a formula I. The small-molecule inhibitor provided by the invention has an excellent inhibition effect on TDG.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to compounds that inhibit the activity of TDG, their preparation methods and applications. Background Art

[0002] Human thymine DNA glycosylase (TDG), as a DNA glycosylase, can mediate DNA repair through the DNA base-excision repair (BER) pathway. When G·T or G·U mismatches occur in the DNA double strand, TDG can recognize the mismatched base, hydrolyze the N-glycosidic bond of U or T, and form an apurinic / apyrimidinic site (AP site). TDG can also promote the binding of apurinic / apyrimidinic endonuclease 1 (APE1) to the AP site, cut the phosphodiester bond at the 5'-end of the abasic deoxynucleotide, and finally repair the DNA after other proteins and bases involved in the repair are added.

[0003] TDG is a key enzyme in the DNA active demethylation pathway mediated by the cooperation of oxidation and the BER pathway. In the TET-TDG-mediated DNA active demethylation mechanism, 5-methylcytosine (5mC) is oxidized to 5-carboxylcytosine (5caC) under the action of a class of TET (ten-eleven-translocation protein) dioxygenases. The TDG enzyme specifically recognizes and excises 5caC, and then initiates the BER pathway to replace the original 5mC with cytosine, thereby achieving DNA demethylation. DNA methylation is an important epigenetic modification method. TDG participates in epigenetic regulation by mediating DNA active demethylation and plays an important role in gene expression regulation, embryonic growth and development, hematopoietic stem cell differentiation, etc.

[0004] TDG can promote tumorigenesis and may be a potential target for cancer treatment. Studies have shown that TDG is overexpressed in some human colorectal carcinoma (CRC) patients. TDG acts as a positive regulator of the WNT signal by serving as an adaptor protein for the transcription factor TCF4 and recruiting CBP / p300. Stable transfection of TDG shRNA into several CRC cell lines inhibited cell growth. Importantly, stable knockdown of TDG expression reduced the tumorigenic ability of CRC cells in xenograft assays, indicating that TDG is essential for CRC cell proliferation in vivo. In addition, knockdown of TDG can inhibit tumor formation in melanoma cell lines in xenograft models, indicating that TDG activity is crucial for tumor induction and / or progression. Therefore, it is very necessary and meaningful to develop specific small molecule inhibitors targeting TDG. Summary of the Invention

[0005] The object of the present invention is to provide a highly efficient small molecule inhibitor targeting TDG.

[0006] In the first aspect of the present invention, there is provided a compound represented by the following formula 1, or its deuterated product, stereoisomer, tautomer, or its pharmaceutically acceptable salt:

[0007]

[0008] R1 is selected from the group consisting of: OH, H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 3-12 membered heterocycle, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted -O-3-12 membered heterocycle, substituted or unsubstituted -C1-C6 alkyl-phenyl, substituted or unsubstituted -O-phenyl, substituted or unsubstituted C1-C4 alkyl-C(O)-, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C6 alkyl-NH-, (substituted or unsubstituted C1-C6 alkyl)2-N-, -O(CH2) s R 10 , or -S(CH2) s R 10 ; s is 0, 1, 2 or 3; R 10 is selected from the group consisting of: H, substituted or unsubstituted C 3-8 carbocycle, substituted or unsubstituted 3-8 membered heterocycle, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl;

[0009] Each R2 is independently selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl;

[0010] R3 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 12 cycloalkyl, or (C1-C6 alkyl)C(O)R8, (C1-C6 alkyl)C(O)NHR8, (C1-C6 alkyl)C(O)N(substituted or unsubstituted C1-C6 alkyl)R8, (C1-C6 alkyl)C(O)OR8; said R8 is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted group selected from the group consisting of: -(CH2) m NHC(O)(CH2) n R 13 、-(CH2)CHR9NHC(O)(CH2) n R 13 、CHR9(CH2)NHC(O)(CH2) n R 13 ; said R9 is selected from the group consisting of: H, -COOH, -CONHR 12 、-CONHCH2R 12 、-CONH(CH2CH2O) m (CH2) n COOH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C 10 carbocyclic ring, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaryl ring; R 12 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl ring; said R 13 is selected from the group consisting of: substituted or unsubstituted C3-C 10 carbocyclic ring;

[0011] Each of m and n is independently 0, 1, 2 or 3;

[0012] R4 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 amino, substituted or unsubstituted C6-C 10aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycle, substituted or unsubstituted 5- to 12-membered heteroaryl, substituted or unsubstituted -O-5- to 12-membered heteroaryl,

[0013] Alternatively, R3 and R4 together with the carbon atom to which they are attached form a structure selected from the group consisting of: a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5- to 10-membered heteroaromatic ring, a substituted or unsubstituted C3-C8 carbocyclic ring, or a substituted or unsubstituted 3- to 10-membered heterocycle;

[0014] R5 and R6 are each independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted 5- to 10-membered heteroaromatic ring, substituted or unsubstituted C3-C8 carbocyclic ring, or substituted or unsubstituted 3- to 10-membered heterocycle; or R5 and R6 together with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 12-membered carbocyclic ring;

[0015] R6' is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl; or R6 and R6' together form =CH2

[0016] X is selected from O or S;

[0017] Z is selected from O, S or NR 14 ; wherein, R 14 is H or C1-C4 alkyl;

[0018] R7 is selected from the group consisting of: H, substituted or unsubstituted C1-C 12 alkyl, or C(O)R 11 、C(O)OR 11 、-CH2OC(O)OR 11 、-S(O)2NHR 11 ;

[0019] The said R 11 is selected from the group consisting of: H, substituted or unsubstituted C1-C 16 alkyl, substituted or unsubstituted C6-C 10 aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5- to 8-membered heterocyclic group;

[0020] Unless otherwise specified, in the above formulas, the heteroaryl ring, heteroaryl group, heterocyclic ring or heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, S or O; the aryl ring, aryl group, heteroaryl ring or heteroaryl group can be a monocyclic or fused ring; the carbocyclic ring, cycloalkyl group, heterocyclic ring or heterocyclic group can be a monocyclic, spirocyclic, bridged or spiro ring; the carbocyclic ring, heterocyclic ring or heterocyclic group can be saturated or partially unsaturated, but not aromatic.

[0021] The term "substituted" means that a hydrogen atom on the corresponding group is substituted by one or more substituents selected from the following group: deuterium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C2-C 12 alkoxycarbonyl, C1-C6 aldehyde group, (C1-C6 alkyl)3Si, amino, C1-C6 amide group, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkyl-amino, C1-C 12 alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 acyl, unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or C1-C4 alkyl-substituted C1-C4 alkyl-OC(O)NH-, unsubstituted or halogenated C1-C4 alkyl-SO-, unsubstituted or C1-C4 alkyl-substituted 5-7 membered heterocyclic ring, or phenyl (which may have 1-5 substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy).

[0022] In another preferred embodiment, R1 is selected from the following group: halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaryl ring, substituted or unsubstituted -O-3-12 membered heterocyclic ring, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C6 alkyl-NH-, (substituted or unsubstituted C1-C6 alkyl)2-N-, or -O(CH2) s R 10 .

[0023] In another preferred embodiment, the compound of formula I has the structure shown in formula II as follows:

[0024]

[0025] Wherein, the A ring is a substituted or unsubstituted C6-C10 aryl ring, a substituted or unsubstituted 5-10 membered heteroaryl ring, a substituted or unsubstituted C3-C8 carbocyclic ring, or a substituted or unsubstituted 3-10 membered heterocyclic ring; preferably, the A ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered heteroaryl ring.

[0026] In another preferred embodiment, the compound has the structure shown in Formula IV below:

[0027]

[0028] Wherein, the B ring is a substituted or unsubstituted C3-C8 carbocyclic ring, or a substituted or unsubstituted 3- to 10-membered heterocyclic ring; preferably, the B ring is a substituted or unsubstituted C3-C6 carbocyclic ring, or a substituted or unsubstituted 3- to 8-membered heterocyclic ring; wherein, the carbocyclic ring or heterocyclic ring can be saturated or partially unsaturated.

[0029] In another preferred embodiment, the compound has the structure shown in Formula V below:

[0030]

[0031]

[0032] Wherein, the D ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5- to 10-membered heteroaromatic ring, a substituted or unsubstituted C3-C8 carbocyclic ring, or a substituted or unsubstituted 3- to 10-membered heterocyclic ring.

[0033] In another preferred embodiment, the compound has the structure shown in Formula VI or VII below:

[0034]

[0035] Wherein, Y is N or CH; Y1 and Y2 are each independently selected from the group consisting of: CHR 15 , NR 15 , O or S; t is 1 or 2; wherein the R 15 is selected from the group consisting of: deuterium, halogen, hydroxyl, carboxyl, mercapto, amino, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.

[0036] In another preferred embodiment, R3 is selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl.

[0037] In another preferred embodiment, R5 and R6 are each independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl; or R5 and R6 and the carbon atom to which they are attached together form a substituted or unsubstituted 3- to 6-membered carbocyclic ring.

[0038] In another preferred embodiment, R3 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 12cycloalkyl, or (C1-C6 alkyl)C(O)R8, (C1-C6 alkyl)C(O)NHR8, (C1-C6 alkyl)C(O)N(substituted or unsubstituted C1-C6 alkyl)R8, (C1-C6 alkyl)C(O)OR8; R8 is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted group selected from the group consisting of: -(CH2) m NHC(O)(CH2) n R 13 、-(CH2)CHR9NHC(O)(CH2) n R 13 、CHR9(CH2)NHC(O)(CH2) n R 13 ; R9 is selected from the group consisting of: H, -COOH, -CONHR 12 、-CONHCH2R 12 、-CONH(CH2CH2O) m (CH2) n COOH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C 10 carbocyclic ring, substituted or unsubstituted 3- to 12-membered heterocyclic ring, substituted or unsubstituted 5- to 12-membered heteroaryl ring; R 12 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl ring; the said R 13 is selected from the group consisting of: substituted or unsubstituted C3-C 10 carbocyclic ring;

[0039] m and n are each independently 0, 1, 2 or 3;

[0040] R4 is selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -O-5- to 12-membered heteroaryl ring;

[0041] Alternatively, R3 and R4 and the carbon atom to which they are attached together form a substituted or unsubstituted C6-C10 aryl ring, or a substituted or unsubstituted 5- to 10-membered heteroaryl ring.

[0042] In another preferred embodiment, the compound has the structure shown in Formula III below:

[0043]

[0044] Preferably, the compound has a structure represented by the following formula III-A or III-B:

[0045]

[0046] Preferably, the compound has any one of the structures selected from the following group:

[0047]

[0048] In another preferred embodiment, the compound has a structure represented by the following formula IX:

[0049]

[0050] Preferably, the compound has a structure represented by the following formula IX-A or IX-B:

[0051]

[0052] Preferably, the compound has any one of the structures selected from the following group:

[0053]

[0054] In another preferred embodiment, the compound has a structure represented by the following formula X:

[0055]

[0056] Preferably, the compound has a structure represented by the following formula X-A or X-B:

[0057]

[0058] Preferably, the compound has any one of the structures selected from the following group:

[0059]

[0060] The second aspect of the present invention provides a pharmaceutical composition comprising (i) the compound as described in the first aspect and (ii) a pharmaceutically acceptable carrier.

[0061] The third aspect of the present invention provides the use of a compound as described in the first aspect, or its deuterated product, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in the second aspect, for the preparation of a medicament for treating and / or preventing a disease associated with abnormal TDG expression.

[0062] In another preferred embodiment, the disease associated with abnormal TDG expression is a tumor.

[0063] In another preferred embodiment, the tumor is selected from the group consisting of: lung cancer, acute leukemia, chronic leukemia, colorectal cancer, breast cancer, thyroid tumor, lymphoma, cholangiocarcinoma, liver cancer, pancreatic cancer, bronchial cancer, esophageal cancer, skin cancer, oral cancer, gastric cancer, urogenital tract tumors, central and peripheral nervous system tumors, or a combination thereof.

[0064] In another preferred embodiment, the tumor is selected from the group consisting of: melanoma, acute myeloid leukemia, small cell lung cancer, non-small cell lung cancer.

[0065] The fourth aspect of the present invention provides a method for inhibiting TDG activity, the method comprising the steps of:

[0066] Contacting a subject with an effective amount of a compound as described in the first aspect, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a crystal form thereof, or a solvate thereof, or a pharmaceutical composition as described in the second aspect, thereby inhibiting TDG activity.

[0067] In another preferred embodiment, the method is in vitro, non-therapeutic and non-diagnostic.

[0068] The fifth aspect of the present invention provides a method for treating and / or preventing a disease associated with TDG overexpression, the method comprising the steps of:

[0069] Administering to a subject an effective amount of a compound as described in the first aspect, or a salt thereof, or an isomer thereof, or a pharmaceutical composition as described in the second aspect.

[0070] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 Shows the inhibitory IC of compound 14 on the in vitro proliferation of p53 mutant and wild-type tumor cell lines 50 . DETAILED DESCRIPTION OF THE INVENTION

[0072] The inventors of the present invention, through extensive and in-depth research, unexpectedly discovered for the first time a class of compounds with TDG inhibitory activity. Based on this, the present invention was completed.

[0073] TERMS

[0074] In the present invention, the halogen is F, Cl, Br or I.

[0075] In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art. In the present invention, unless otherwise specified, all chemical formulas are intended to cover any possible optical or geometric isomers (such as R-type, S-type or racemates, or cis-trans isomers of olefins, etc.).

[0076] In the present invention, the term "C1-C6 alkyl" refers to a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0077] In the present invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.

[0078] In the present invention, the term C1-C6 amino refers to "C1-C6 alkyl-NH-" and "(C1-C6 alkyl)2N-", or similar structures.

[0079] In the present invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched-chain alkenyl having 2 to 6 carbon atoms and containing one double bond, including, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, etc.

[0080] In the present invention, the term "C2-C6 alkynyl" refers to a straight-chain or branched-chain alkynyl having 2 to 6 carbon atoms and containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, etc.

[0081] In the present invention, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, etc. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

[0082] In the present invention, the term "C1-C12 alkoxycarbonyl" refers to an alkoxycarbonyl having 1 to 12 carbon atoms in the alkyl chain, including, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.

[0083] In the present invention, the term "C1-C12 alkylaminocarbonyl" refers to an alkylaminocarbonyl having 1 to 12 carbon atoms in the alkyl chain, including, without limitation, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl, etc.

[0084] In the present invention, the terms "aromatic ring" or "aryl" have the same meaning. Preferably, "aryl" is "C6-C12 aryl" or "C6-C10 aryl". The term "C6-C12 aryl" refers to an aromatic cyclic group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "C6-C10 aryl" has a similar meaning.

[0085] In the present invention, the terms "aromatic heterocycle", "heteroaromatic ring" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. For example, furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is the heteroaryl ring. The heteroaryl can be optionally substituted or unsubstituted.

[0086] In the present invention, the term "3- to 12-membered heterocyclic group" refers to a saturated or unsaturated 3- to 12-membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxolanyl, etc. The term "3- to 7-membered heterocyclic group" has a similar meaning.

[0087] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by specific substituents. The specific substituents are the substituents described correspondingly in the foregoing or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group can have a substituent selected from a specific group at any substitutable site of the group, and the substituents can be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, can be connected to another ring, such as a cycloalkyl, to form a spirobicyclic system. For example, the two rings have a common carbon atom. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable combinations. The substituents are, for example (but not limited to): C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde group, C2-10 acyl group, C2-10 ester group, C1-C12 alkoxycarbonyl group, amino group, alkoxy group, C1-10 sulfonyl group, etc.

[0088] The compound of formula (I) as a TDG inhibitor

[0089] The present invention provides a class of compounds having TDG inhibitory activity:

[0090]

[0091]

[0092] Each group has the definition as described above in the text.

[0093] Drug Compositions and Administration Methods

[0094] Since the compounds of the present invention have excellent biological activities, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and drug compositions containing the compounds of the present invention as the main active ingredient can be used for treating, preventing and alleviating related diseases caused by abnormal activity or expression level of TDG.

[0095] The drug compositions of the present invention comprise a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the drug composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, 5 - 200 mg of the compound of the present invention per dose. Preferably, the said "one dose" is one capsule or one tablet.

[0096] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that each component in the composition can be blended with the compound of the present invention and with each other without significantly reducing the drug efficacy of the compound. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ) wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0097] There is no particular limitation on the administration mode of the compounds or drug compositions of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0098] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier) such as sodium citrate or calcium phosphate dibasic, or with the following components: (a) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0099] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and release of the active compound or compounds in such compositions can be delayed and released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric and wax-like substances. Optionally, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0100] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0101] In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfumes.

[0102] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar, or mixtures of these substances.

[0103] Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and sterile powders for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0104] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required, if necessary.

[0105] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. In some preferred embodiments, the compounds of the present invention can form PROTACs together with other small molecule compounds, or be administered as ADCs in combination with other macromolecular compounds such as monoclonal antibodies.

[0106] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 5 - 500 mg. Of course, the specific dosage should also consider factors such as the route of administration and the health condition of the patient, which are within the scope of the skills of a skilled physician.

[0107] The present invention will be further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise stated, percentages and parts are calculated by weight.

[0108] Abbreviations:

[0109]

[0110]

[0111] The raw materials can be obtained through commercial channels or prepared by methods known or disclosed in the art.

[0112] Purification of intermediates and compounds is carried out by conventional chemical experimental operations such as normal-phase or reverse-phase chromatography or recrystallization. Normal-phase chromatography is a pre-packed silica gel chromatography column or preparative thin-layer chromatography. The silica gel chromatography column is mainly a glass column or a flash column chromatography instrument. The models of the flash column chromatography instrument are Or other brands. The mobile phase for normal-phase chromatography is selected and proportioned from petroleum ether / ethyl acetate, dichloromethane / methanol or other suitable solvents for elution. Reverse-phase preparative liquid chromatography uses a C18 column and is carried out with a preparative liquid chromatograph or a flash column chromatograph, detected by 214 nM and 254 nM or a preparative liquid chromatography-mass spectrometry instrument, and gradient elution is carried out with water / acetonitrile containing 0.1% hydrochloric acid, water / acetonitrile, water / acetonitrile containing 0.1% ammonium bicarbonate, water / acetonitrile containing 0.1% formic acid, water / acetonitrile containing 0.1% ammonia, water / acetonitrile containing 0.1% trifluoroacetic acid or other suitable solvent systems as the mobile phase.

[0113] Prep HPLC was carried out on a Gilson preparative HPLC system (GX-281). Representative prep HPLC conditions were as follows: ① FA method: Column: Boston Prime C18 150*30mm*5um; mobile phase: [water(0.225% FA)-ACN]; ② FA method - A: Phenomenex Gemini C18 250*50mm*10um; mobile phase: [water(0.225% FA)-ACN]; ③ FA method - B: Phenomenex C18 80*30mm*5um; mobile phase: [water(0.225FA)-ACN].

[0114] The conventional post-treatment operations described in the text are as follows: Combine the organic phases, dry the organic phases with anhydrous sulfuric acid or anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The second conventional post-treatment operation described in the text is: Combine the organic phases, wash the organic phases with saturated brine (in extremely rare cases, wash with a 30% lithium chloride solution), dry with anhydrous sulfuric acid or anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent or. Unless otherwise specified, the reaction time indicated for the chemical reaction is the time when LCMS detection or TLC detection or other suitable detection methods show that the reaction has reacted completely or the raw materials have completely disappeared.

[0115] The structural characterization of intermediates and compounds was carried out by nuclear magnetic resonance (NMR) and liquid chromatography - mass spectrometry (LCMS). The nuclear magnetic resonance spectrometer used for NMR was Bruker Ascend TM - 400MHz or Bruker UltrashieldPlus 400MHz or other models. The solvents used were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol or other labeled deuterated solvents. The spectral data was reported in the form: chemical shift δ (number of peaks, coupling constant J (Hz), number of hydrogens). Tetramethylsilane was used as the internal standard for chemical shift, and its chemical shift was set to zero (δ, 0 ppm). The meanings of some abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak).

[0116] The representative methods for liquid chromatography - mass spectrometry (LCMS) in the structural characterization of intermediates and compounds are as follows:

[0117] LCMS was carried out on an Agilent MSD mass spectrometer connected to an Agilent 1260 system, and detected by ultraviolet (UV, 254 or 220 nm) and mass spectrometry (MS, ESI + ).

[0118] Method 1: 5 - 95 AB, column: Agilent Pursult 5C18 20 * 2.0 mm, solvent A: 0.0375% aqueous TFA solution, solvent B: 0.1125% TFA acetonitrile solution, from 5% solvent B to 95% solvent B in 0.7 minutes, hold for 0.4 minutes, total 1.5 minutes; flow rate: 1.5 mL / min; column temperature 50 °C.

[0119] Method 2: 5 - 95 AB_3min_220&254_Agilent, column: Agilent Poroshell 120EC - C18 2.7um 3.0 * 30 mm, solvent A: 0.0375% aqueous TFA solution, solvent B: 0.1125% TFA acetonitrile solution, from 5% solvent B to 80% solvent B in 1.2 minutes, from 80% solvent B to 95% solvent B in 1.3 minutes, hold for 0.5 minutes, total 3 minutes; flow rate: 1.5 mL / min; column temperature 50 °C.

[0120] Method 3: 0 - 100 AB_QC_220&254 column: ACQUITY UPLC BEH C18 50 * 2.1 mm, 1.7um, solvent A: 0.1% aqueous TFA solution, solvent B: 0.1% TFA acetonitrile solution, from 0% solvent B to 100% solvent B in 1 minute, hold for 0.2 minutes, total 1.5 minutes; flow rate: 1.0 mL / min; column temperature 40 °C.

[0121] Method 4: 10 - 80 AB_4 min_220 & 254_Shimadzu, column: Nano Chrom 120 C18 3.0 * 30 mm, 3 um, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, 10% solvent B to 80% solvent B in 3 minutes, hold for 0.5 minutes, total 4 minutes; flow rate: 0.8 mL / min; column temperature 50 °C.

[0122] Method 5: 5 - 95 AB_1 min_220 & 254_Agilent, column: Agilent Poroshell 120 EC - C18 2.7 um 3.0 * 30 mm, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, 5% solvent B to 95% solvent B in 0.4 minutes, hold for 0.3 minutes, total 1 minute; flow rate: 2 mL / min; column temperature 50 °C.

[0123] Method 6: 0 - 95 AB_1.5 min_220 & 254_Agilent, column: Waters, Xbridge C18 30 * 2.1 mm, 3.5 um, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, 0% solvent B to 95% solvent B in 0.6 minutes, hold for 0.8 minutes, total 1.5 minutes; flow rate: 1.2 mL / min; column temperature 40 °C.

[0124] Method 7: 10 - 80 CD_3 MIN_220 & 254_Shimadzu, column: XBridge C18 3.5 um 2.1 * 30 mm, solvent A: 0.025% ammonia aqueous solution, solvent B: acetonitrile, 10% solvent B to 80% solvent B in 2 minutes, hold for 0.48 minutes, total 3 minutes; flow rate: 1 mL / min; column temperature 50 °C.

[0125] Method 8: 10 - 80 AB_7 min_220 & 254_Shimadzu column: Xtimate C18 2.1 * 30 mm, 3 um, solvent A: 0.0375% TFA aqueous solution, solvent B: 0.1125% TFA acetonitrile solution, 10% solvent B to 80% solvent B in 6 minutes, hold for 0.5 minutes, total 7 minutes; flow rate: 0.8 mL / min; column temperature 50 °C.

[0126] Representative catalytic hydrogenation operation: Dissolve the compound in the corresponding solvent, such as EA or THF, add palladium on carbon (10% content, about 0.1 equivalent) or palladium hydroxide on carbon (20% content, about 0.1 equivalent), and fully displace hydrogen in the reaction mixture. Stir at 25 °C under a hydrogen atmosphere of 15 Psi until LCMS shows that the reaction is complete. Filter the reaction solution by suction, concentrate it under reduced pressure to dryness, and purify to obtain the product.

[0127] Method 1 for the synthesis of Compound 14 in Example 1

[0128]

[0129] Step 1:

[0130]

[0131] Add H2O (25 mL), ethyl diazoacetate (14-a-1) (3.50 g, 24.54 mmol, 80% purity, 1 eq), and phenyl vinyl sulfide (5.01 g, 36.81 mmol, 1.5 eq) to a mixture of (S,S)-(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-diaminocobalt (CAS: 188264-84-8, 370 mg, 613.48 μmol, 0.025 eq) and (R,R)-(-)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt (CAS: 176763-62-5, 370 mg, 613.48 μmol, 0.025 eq) that has been degassed and filled with nitrogen, and react at 40 °C for 24 hours. TLC shows that the reaction is complete, and two products are formed (PE:EA = 8:1, Rf = 0.4, 0.5). Cool to 25 °C, degas and flush with oxygen several times, and then react at 25 °C for 1 hour. Filter through diatomaceous earth and rinse with DCM (20 mL * 2), and extract the aqueous phase with DCM (50 mL * 2). Combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel chromatography column ( 120 g Silica Flash Column, 0~0.1, 2, 3% EA / PE, 80 mL / min) to obtain a red oil 14-b-1 (cis structure, 3.08 g, 13.85 mmol, 56.46% yield). 11H NMR (400 MHz, CDCl3) Shift 7.35 - 7.42 (m, 2H), 7.26 - 7.30 (m, 2H), 7.13 - 7.21 (m, 1H), 4.07 (q, J = 7.11 Hz, 2H), 2.72 (q, J = 7.78 Hz, 1H), 2.22 - 2.35 (m, 1H), 1.45 - 1.53 (m, 2H), 1.12 (t, J = 7.03 Hz, 3H).

[0132] Step 2:

[0133]

[0134] Within one hour, m-CPBA (21.9 g, 101.96 mmol, 80% purity, 1.48 eq) was added portionwise to a solution of compound (14-b-1) (15.3 g, 68.83 mmol, 1 eq) in DCM (400 mL) at 0 °C, and the reaction was carried out at 25 °C for 16 hours. After completion of the reaction, an aqueous solution of KOH (3 M, 500 mL) was added. The aqueous phase was extracted with DCM (300 mL * 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography ( 220 g Silica Flash Column, 50 - 80% EA / PE, 100 mL / min) to obtain a brown oil 14-c-1 (9.8 g, 41.12 mmol, 59.75% yield). (ESI) m / z = 238.9 [M + H] + . 1 1H NMR (400 MHz, CDCl3) δ δ 7.62 - 7.72 (m, 2H), 7.50 - 7.55 (m, 3H), 4.16 - 4.28 (m, 2H), 2.62 (dt, J = 6.60, 8.36 Hz, 1H), 2.14 (dt, J = 6.49, 8.20 Hz, 1H), 2.03 - 2.11 (m, 1H), 1.64 (dt, J = 5.72, 8.25 Hz, 1H), 1.31 (t, J = 7.15 Hz, 3H).

[0135] Step 3:

[0136]

[0137] To a solution of compound (14-a) (1.60 g, 5.53 mmol, 1 eq) and trimethyl boroxine (4.17 g, 16.60 mmol, 4.64 mL, 50% purity, 3.0 eq) in DMF (40 mL) was added K2CO3 (2.29 g, 16.60 mmol, 3.0 eq), and the mixture was purged with nitrogen several times. Pd(dppf)Cl2 (202 mg, 276.70 μmol, 0.05 eq) was added, and the reaction was carried out at 100 °C for 16 h under nitrogen protection. After completion of the reaction, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography ( 24 g Silica Flash Column, 0 - 25% EA / PE, 35 mL / min) to give a yellow solid (14-b) (850 mg, 3.79 mmol, yield 68.49%). (ESI) m / z = 225.1 (M + 1) + .

[0138] Step 4:

[0139]

[0140] A solution of compound (14-b) (950 mg, 4.24 mmol, 1 eq) in DCM (10 mL) and TFA (2 mL) was reacted at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give a red oil, compound (14-c) (3.21 g, 13.47 mmol, 97.22% yield), which was directly used in the next step.

[0141] Step 5:

[0142]

[0143] To a solution of compound (14-c) (722 mg, 4.34 mmol, 1 eq) and triisopropylchlorosilane (1.26 g, 6.52 mmol, 1.39 mL, 1.5 eq) in THF (10 mL) were added imidazole (591 mg, 8.69 mmol, 2.0 eq) and DIEA (1.12 g, 8.69 mmol, 1.51 mL, 2.0 eq), and the reaction was carried out at 25 °C for 2 h. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with EtOAc (30 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography ( 24 g Purified by silica flash column (0 - 10% EA / PE, 35 mL / min) to obtain a colorless oil (14 - d) (1.23 g, 3.81 mmol, 87.78% yield). 1 H NMR (400 MHz, CDCl3) Shift 10.29 (s, 1H), 7.65 (s, 1H), 6.40 (s, 1H), 3.86 (s, 3H), 2.19 (s, 3H), 1.31 - 1.39 (m, 3H), 1.08 (s, 18H). (ESI) m / z = 323.3 (M + 1) + .

[0144] Step 6:

[0145]

[0146] At - 78 °C, add isopropylmagnesium chloride solution (2 M, 2.00 mL, 1.5 eq) to a solution of compound (14 - c - 1) (635 mg, 2.67 mmol, 1 eq) in THF (25 mL), stir at - 78 °C for 15 minutes. Add a solution of compound (14 - d) (860 mg, 2.67 mmol, 1.0 eq) in toluene (3 mL), react at 0 °C for 3 hours. After the reaction is completed, quench with saturated aqueous NH4Cl solution (20 mL), extract with EtOAc (20 mL * 3). Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue is purified by silica chromatography column ( 24 g Silica Flash Column, 0 - 10% EA / PE, 35 mL / min) to obtain a colorless oil compound (14 - e) (220 mg, 563.25 μmol, 21.12% yield). 1 H NMR (400 MHz, CDCl3) 6.95 - 7.05 (m, 1H), 6.37 - 6.45 (m, 1H), 5.83 (d, J = 4.77 Hz, 0.3H), 5.49 (s, 0.5H), 4.60 (s, 0.3H), 3.79 - 3.81 (m, 3H), 2.63 - 2.68 (m, 0.3H), 2.18 - 2.26 (m, 4.4H), 1.25 - 1.38 (m, 4H), 1.01 - 1.17 (m, 19H). (ESI) m / z = 391.2 (M + 1) + .

[0147] Step 7:

[0148]

[0149] To a solution of compound (14-e) (180 mg, 460.84 μmol, 1 eq) in THF (5 mL) was added triethylamine trihydrofluoride (59.4 mg, 368.68 μmol, 60.09 μL, 0.8 eq), and the reaction was carried out at 25 °C for 3 h. After completion of the reaction, the reaction was quenched by adding saturated aqueous NaHCO3 solution (5 mL), and extracted with EtOAc (5 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography ( 12 g Silica Flash Column, 0 - 30% EA / PE, 35 mL / min) to obtain the pink solid compound 14 (70 mg, 283.89 μmol, 61.60% yield, 95% purity). (ESI) m / z = 235.0 (M + 1) + .

[0150] Referring to the method in steps 5 to 7 of the synthesis method of compound 14 above, the starting materials in the following table were used for the reaction to obtain the corresponding final product compounds.

[0151]

[0152] Example 2 Method 2 for the synthesis of compound 14

[0153]

[0154] Step 1:

[0155]

[0156] To a solution of compound (14-c) (5.0 g, 30.09 mmol, 1 eq) in DMF (75 mL) was added K2CO3 (12.5 g, 90.27 mmol, 3.0 eq) and 3-bromo-1-propene (4.73 g, 39.12 mmol, 1.3 eq), and the reaction was carried out at 25 °C for 3 h. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography ( 80 g

[0157] Silica Flash Column, 0 - 10% EA / PE, 65 mL / min) to obtain the white solid compound (14-f) (5.3 g, 25.70 mmol, 85.41% yield). 11H NMR (400 MHz, CDCl3) Shift 10.30 (s, 1H), 7.64 (d, J = 0.61 Hz, 1H), 6.40 (s, 1H), 6.09 m, 1H), 5.48 (m, 1H), 5.36 (m, 1H), 4.65 (td, J = 1.53, 5.01 Hz, 2H), 3.91 (s, 3H), 2.19 (s, 3H).

[0158] Step 2:

[0159]

[0160] At -78 °C, isopropylmagnesium chloride solution (2 M, 25.46 mL, 1.5 eq) was added to a solution of compound (14-c-1) (8.09 g, 33.94 mmol, 1 eq) in THF (210 mL), and the mixture was stirred at -78 °C for 60 minutes. A solution of compound (14-f) (7.0 g, 33.94 mmol, 1.0 eq) in toluene (20 mL) was added, and the reaction was carried out at 0 °C for 3 hours. After completion of the reaction, the reaction was quenched with saturated aqueous NH4Cl solution (200 mL), and extracted with EtOAc (200 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography ( 220 g

[0161] Silica Flash Column, 0 - 15% EA / PE, 30 mL / min) to give compound (14-g) as a colorless oil (4.8 g, 16.8 mmol, 49.49% yield). 1 1H NMR (400 MHz, CDCl3) Shift 6.96 - 7.08 (m, 1H), 6.47 (s, 1H), 6.00 - 6.18 (m, 1H), 5.84 (d, J = 4.62 Hz, 0.24H), 5.51 (s, 0.7H), 5.46 (qd, J = 1.65, 17.28 Hz, 1H), 5.27 - 5.36 (m, 1H), 4.59 (td, J = 1.68, 5.01 Hz, 2H), 3.82 - 3.90 (m, 3H), 2.61 - 2.72 (m, 0.2H), 2.12 - 2.30 (m, 4.8H), 1.20 - 1.40 (m, 1H), 0.96 - 1.10 (m, 1H), 0.80 - 0.90 (m, 0.28H). (ESI) m / z = 275.2 (M + 1) +

[0162] Step 3:

[0163]

[0164] To a solution of compound (14-g) (4.53 g, 16.53 mmol, 1 eq) in THF (100 mL) were added Pd(OAc)2 (1.11 g, 4.96 mmol, 0.3 eq) and PPh3 (5.2 g, 19.84 mmol, 1.2 eq), and the reaction was carried out at 25 °C for 20 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography ( 120 g Silica Flash Column, 0-30% EA / PE, 60 mL / min) and then triturated with MTBE:PE (1:1, 10 mL) to give a white solid compound (14) (990 mg, 4.23 mmol, 25.64% yield). (ESI) m / z = 235.1 (M+1) + . 1 1H NMR (400 MHz, DMSO-d6) Shift 9.19 - 9.67 (m, 1H), 6.82 - 6.98 (m, 1H), 6.44 - 6.54 (m, 1H), 5.73 (d, J = 4.65 Hz, 0.2H), 5.39 (s, 0.8H), 3.64 - 3.79 (m, 3H), 2.12 - 2.28 (m, 2H), 1.98 - 2.11 (m, 3H), 1.29 (dt, J = 4.46, 8.16 Hz, 0.8H), 1.00 - 1.10 (m, 0.2H), 0.96 (q, J = 4.28 Hz, 0.8H), 0.71 (br d, J = 3.30 Hz, 0.2H)

[0165] Referring to the methods of Steps 2 and 3 in Example 2, the corresponding final product compounds were obtained by two-step reaction with (14-f) using the following starting materials to replace (14-c-1).

[0166]

[0167] The synthetic method of starting material 44-A involved in the above table is as follows:

[0168]

[0169] Referring to the method of Step 2 in Example 1, using 44-B (600 mg, 2.40 mmol) as the starting material for the reaction gave a colorless oil 44-A (540 mg, yield 84.59%). 11H NMR (400 MHz, CDCl3) δ 7.63 - 7.85 (m, 2H), 7.38 - 7.61 (m, 3H), 4.10 - 4.37 (m, 2H), 2.38 - 2.55 (m, 1H), 1.90 - 2.15 (m, 1H), 1.52 - 1.71 (m, 3H), 1.22 - 1.42 (m, 4H), 1.13 (s, 2H).

[0170] Referring to the method of Example 2, a three-step reaction was carried out starting from the following starting materials to obtain the corresponding final product compound.

[0171]

[0172]

[0173]

[0174]

[0175]

[0176] The synthetic methods of the starting materials 284-A and 285-A involved in the above table are as follows:

[0177]

[0178] Step 1: Under microwave conditions, a mixture of compound 2-methoxy-4-(prop-2-enyloxy)benzene-1-carbaldehyde (200 mg, 1.04 mmol, 1 eq) in N,N-dimethylaniline (2 mL) was stirred at 180 °C for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc (15 mL), washed with 1 M HCl (3 mL * 3), and the organic phase was subjected to conventional post-treatment operation two to obtain a crude product. The crude product was purified by silica gel column chromatography (EA / PE, EA from 7 to 15%) to obtain a grayish-white solid compound 284-B (50 mg, yield 25%) and a yellow solid compound 285-B (82.5 mg, yield 41.3%).

[0179] Compound 284-B: 1 1H NMR (400 MHz, CDCl3) δ (ppm) 10.22 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.39 (br s, 1H), 6.06 (ddt, J = 5.9, 10.5, 16.8 Hz, 1H), 5.09 - 5.25 (m, 2H), 3.91 (s, 3H), 3.47 - 3.60 (m, 2H).

[0180] Compound 285-B: 1 H NMR(400MHz,CDCl3)δ(ppm)10.28(s,1H),7.64(s,1H),6.46(s,1H),6.06 - 6.11(m,1H),5.92 - 6.06(m,1H),5.16 - 5.26(m,2H),3.88(s,3H),3.39(d,J=6.4Hz,2H)

[0181] Compound 284-A: Referring to the method for synthesizing Compound 281-A from Compound 281-B, reaction was carried out with 284-B (200 mg) to obtain Compound 284-A (200 mg) as a yellow oil. The crude product was directly used in the next reaction. LC-MS: (ESI) m / z [M + H] + 195.2。 1 H NMR(400MHz,CDCl3)δ(ppm)10.20(s,1H),7.67(d,J=8.4Hz,1H),6.70(d,J=8.6Hz,1H),6.11(br s,1H),3.92(s,3H),2.55 - 2.74(m,2H),1.52 - 1.65(m,2H),0.96 - 1.16(m,3H).

[0182] Compound 285-A: Referring to the method for synthesizing Compound 281-A from Compound 281-B, reaction was carried out with 285-B (330 mg) to obtain Compound 285-A (330 mg) as an off-white solid. The crude product was directly used in the next reaction. LC-MS: (ESI) m / z [M + H] + 195.2。 1 H NMR(400MHz,CDCl3)δ(ppm)10.27(s,1H),7.64(s,1H),6.43(s,1H),6.06(s,1H),3.87(s,3H),2.44 - 2.64(m,2H),1.53 - 1.64(m,2H),0.96(t,J=7.3Hz,3H).

[0183] The synthetic methods of the starting materials 281-A and 281-B involved in the above table are as follows:

[0184]

[0185] Step 1: A mixture of compound 14-f (1.0 g, 4.85 mmol, 1 eq) in N,N-dimethylaniline (8 mL) was stirred at 180 °C for 8 h. TLC showed that only a small amount of the starting material remained unreacted. The reaction mixture was cooled to room temperature, diluted with EtOAc (10 mL), washed with 1 M HCl (10 mL * 3), and the organic phase was subjected to conventional work-up procedures to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE, EA from 0 to 7%) to give the off-white solid compound 281-B (640 mg, 3.10 mmol, 64% yield). LC-MS: (ESI) m / z [M + H] + 207.0。

[0186] Step 2: Compound 281-B (300 mg, 1.45 mmol) was dissolved in EtOAc (30 mL), palladium / carbon (5% content, 60 mg) was added, and the reaction mixture was purged with hydrogen thoroughly. The reaction was stirred at 25 °C under a hydrogen atmosphere of 15 Psi for 2 h. After filtration through diatomaceous earth, the solvent was evaporated under reduced pressure to give the off-white solid compound 281-A (290 mg), and the crude product was directly used for the next reaction. LC-MS: (ESI) m / z [M + H] + 209.1。

[0187] The synthetic method of the starting material 40-A involved in the above table is as follows:

[0188]

[0189] At -78 °C, dichloromethyl methyl ether (410 mg, 3.57 mmol) and a solution of titanium tetrachloride (1.41 g, 7.43 mmol) in DCM (5 mL) were added to a solution of compound 40-B (500 mg, 2.97 mmol) in DCM (10 mL). The reaction mixture was allowed to warm to 25 °C and stirred for 16 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). After conventional work-up procedures II, purification by silica gel column chromatography (EA:PE, EA from 0 to 7%) gave the white solid compound 40-A (440 mg, 75.44% yield). 1 H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.42 (s, 1H), 6.42 (s, 1H), 3.97 (s, 3H), 3.97 (s, 3H), 2.24 (d, J = 0.72 Hz, 3H).

[0190] The synthetic method of the starting material 116-A involved in the above table is as follows:

[0191]

[0192] According to the synthesis method of 40-A, reacting with 116-B (3.0 g, 14.27 mmol) gave purple solid 116-A (2.2 g, yield 64.7%). 1 H NMR (400 MHz, DMSO-d6) Shift 10.80 (s, 1H), 10.11 (s, 1H), 7.45 (s, 1H), 6.54 (s, 1H), 3.82 (s, 3H), 3.57 (s, 3H), 2.71 - 2.78 (m, 2H), 2.53 - 2.60 (m, 2H).

[0193] The synthesis method of the starting material 48-A involved in the above table is as follows:

[0194]

[0195] According to the synthesis method of 40-A, reacting with 48-B (870 mg, 6.39 mmol) gave white solid 48-A (720 mg, yield 68.64%). 1 H NMR (400 MHz, DMSO-d6) δ10.41 (br s, 1H), 9.97 (s, 1H), 7.56 (s, 1H), 6.71 (s, 1H), 2.90 (q, J = 7.46 Hz, 2H), 2.12 (s, 3H), 1.13 (t, J = 7.46 Hz, 3H).

[0196] The synthesis method of the starting material 62-A involved in the above table is as follows:

[0197]

[0198] According to the synthesis method of 40-A, reacting with 62-B (1.06 g, 5.14 mmol) gave brown solid 62-A (432 mg, yield 19.3%, purity 73.3%). LCMS: (ESI) m / z = 235.0 (M + 1) +

[0199] The synthesis method of the starting material 31-A involved in the above table is as follows:

[0200]

[0201] To a solution of compound 30-A (1.9 g, 12.33 mmol) and dimethylamine hydrochloride (3.02 g, 36.98 mmol) in DMF (50 mL) was added K2CO3 (5.11 g, 36.98 mmol). After stirring the reaction at 110 °C for 16 h, it was cooled to room temperature, water (30 mL) was added, and it was extracted with EtOAc and THF (1:1, 50 mL x 3). After conventional post-treatment operations, it was purified by silica gel column chromatography (EA:PE, EA from 0 to 20%) to obtain the yellow solid compound 31-A (820 mg, yield 37.12%). 1 H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.59 (s, 1H), 6.50 (s, 1H), 2.85 (s, 6H), 2.22 (s, 3H)

[0202] The synthetic method of the starting material 162-A involved in the above table is as follows:

[0203]

[0204] Step 1: Referring to the synthetic method of the starting material 30-A, using 162-C (1 g, 4.30 mmol) for the reaction to obtain the yellow oil 162-B (0.95 g, yield 85.7%). LC-MS: (ESI) m / z. [M+H] + 258.1.

[0205] Step 2: Referring to the method of Step 4 in Example 1, using 162-B (0.80 g) for the reaction to obtain the yellow oil 162-A (0.62 g), and the crude product was directly used for the next reaction. LC-MS: (ESI) m / z. [M+H] + 200.1.

[0206] The synthetic method of the starting material 32-A involved in the above table is as follows:

[0207]

[0208] Referring to the method of Step 4 in Example 8-b, reacting 15-A (500 mg, 2.33 mmol) with potassium vinyltrifluoroborate (934 mg, 6.98 mmol) to obtain the off-white solid compound 32-A (250 mg, yield 66.3%). 11H NMR (CDCl3, 400 MHz) δ 10.13 (s, 1H), 7.66 (s, 1H), 7.52 (dd, J = 11.00, 17.36 Hz, 1H), 6.97 (s, 1H), 6.69 (s, 1H), 5.65 (d, J = 17.36 Hz, 1H), 5.46 (d, J = 11.00 Hz, 1H), 2.31 (s, 3H).

[0209] The synthesis method of the starting material 35-A involved in the above table is as follows:

[0210]

[0211] To a mixture of compound 15-A (1 g, 4.65 mmol) in dioxane / water (20 mL, 9 / 1), 35-B (691 mg, 5.58 mmol) and K3PO4 (2.96 g, 13.95 mmol) were added. After degassing and refilling with nitrogen three times, Pd(dppf)Cl2 (170 mg, 232.51 μmol) was added. The mixture was heated to 100 °C and reacted for 16 hours. After cooling to room temperature, the reaction was diluted with saturated brine (50 mL) and extracted with EtOAc (20 mL * 3) and THF (15 mL * 3). After conventional post-treatment operations, a crude product was obtained. The crude product was triturated in DCM (10 mL) and washed with DCM (2 mL * 3) to obtain the white solid compound 35-A (767 mg, yield 77%). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 - 2.28 (m, 3H) 6.77 - 6.84 (m, 1H) 7.72 - 7.86 (m, 1H) 8.80 - 8.90 (m, 2H) 9.19 - 9.28 (m, 1H) 9.66 - 9.75 (m, 1H) 10.82 - 10.94 (m, 1H).

[0212] The synthesis method of the starting material 41-A involved in the above table is as follows:

[0213]

[0214] Referring to the synthesis method of compound 35-A, 15-A (1 g, 4.65 mmol) was reacted with (E)-styreneboronic acid (413 mg, 2.79 mmol, 1.2 eq) to obtain the brown solid 41-A (302 mg, yield 54.51%). 11H NMR (400 MHz, DMSO-d6) δ ppm 2.13 - 2.25 (m, 3H) 7.14 - 7.21 (m, 1H) 7.29 - 7.35 (m, 1H) 7.37 - 7.47 (m, 2H) 7.57 - 7.71 (m, 3H) 8.03 - 8.20 (m, 1H) 10.09 - 10.19 (m, 1H).

[0215] The synthetic method of starting material 37-A involved in the above table is as follows:

[0216]

[0217] To a mixture of compound 15-A (500 mg, 2.33 mmol) in THF (10 mL), Pd(dppf)Cl2 (326 mg, 465 μmol) was added. After degassing and refilling with nitrogen three times, TEA (1.18 g, 11.63 mmol), CuI (44.2 mg, 232.51 μmol) and 37-B (551 mg, 3.02 mmol) were added. The mixture was heated to 70 °C and reacted for 16 hours. After cooling to room temperature, the reaction was diluted with water (5 mL), and the organic phase was separated. After conventional post-treatment operations, the crude product was obtained and purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain yellow solid compound 37-A (450 mg, yield 61.15%). 1 1H NMR (CDCl3, 400 MHz) δ ppm 10.44 (s, 1H) 7.76 (s, 1H) 6.98 (s, 1H) 5.77 (s, 1H) 2.30 (s, 3H) 1.09 - 1.23 (m, 22H).

[0218] The synthetic method of starting material 61-A involved in the above table is as follows:

[0219]

[0220] To a mixture of compound 61-B (980 mg, 4.24 mmol) in toluene (50 mL) / water (5 mL), cyclopropylboronic acid (473 mg, 5.51 mmol) and K3PO4 (2.70 g, 12.7 mmol) were added. The mixture was purged with nitrogen three times, Pd(OAc)2 (50 mg, 223 μmol) and tricyclohexylphosphine (490 mg, 1.75 mmol) were added, and the mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was diluted with 2 mL of saturated brine, and the mixture was extracted with EA (5 mL × 2). After conventional post-treatment operations, the residue was obtained, and the residue was purified by silica gel column chromatography (THF:PE, THF from 0 to 15%) to obtain yellow solid compound 61-A (330 mg, yield 40.48%).1 1H NMR (400 MHz, CDCl3) δ (ppm) 10.26 (s, 1H), 7.64 (d, J = 0.7 Hz, 1H), 6.50 (s, 1H), 3.89 (s, 3H), 1.61 - 1.75 (m, 1H), 0.92 - 1.03 (m, 2H), 0.61 - 0.67 (m, 2H).

[0221] The synthetic method of the starting material 64 - A involved in the above table is as follows:

[0222]

[0223] Step 1: Add NaSCH3 (4.16 g, 59.4 mmol) to a solution of 30 - A (2.50 g, 16.2 mmol) in DMF (50 mL). The mixture was reacted at 120 °C until LC - MS showed that the raw material was completely reacted. Cooled to room temperature, the reaction solution was poured into water (50 mL), and the pH was adjusted to 5 with 50% acetic acid, and then extracted with EA (3×50 mL). After conventional post - treatment operation two, a residue was obtained. The crude product was purified by silica gel thin - layer chromatography (EA:PE, EA from 0 to 25%) to obtain a yellow oil 47 - A (1.5 g, yield 50.7%). 1 1H NMR (400 MHz, DMSO - d6) δ (ppm) 9.87 (s, 1H), 7.62 (s, 1H), 6.80 (s, 1H), 2.38 (s, 3H), 2.13 (s, 3H)

[0224] Step 2: Add m - CPBA (2.79 g, 13.7 mmol, 85% purity) to a solution of compound 64 - C (1.0 g, 5.49 mmol) in DCM (20 mL) in portions at 0 °C, and react at 25 °C for 2 hours. Filtered and dried in vacuo to obtain a white solid compound 64 - A (3.2 g, 35% purity), and the crude product was directly used for the next reaction.

[0225] The synthetic method of the starting material 278 - A involved in the above table is as follows:

[0226]

[0227] Step 1: To a solution of 170 - A (5.0 g, 32.9 mmol) in DMF (50 mL), add K2CO3 (5.0 g, 36.2 mmol, 1.1 eq) and compound 278 - B (4.24 g, 39.4 mmol, 1.2 eq). The mixture is reacted at 40 °C for 3 hours. After cooling to room temperature, add EA (100 mL), filter, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 25%) to obtain the white solid compound 278 - C (7 g, yield 95%). LC - MS: (ESI) m / z. [M + H] + 224.21.

[0228] Step 2: To a solution of compound 278 - C (2 g, 8.96 mmol) and compound 278 - D (695 mg, 4.48 mmol) in 1,2 - dichloroethane (40 mL), add Pd(OAc)2 (201 mg, 896 μmol), silver trifluoroacetate (AgTFA) (198 mg, 896 μmol), and TFA (10.2 g, 89.6 mmol). After stirring at 25 °C for 0.5 hours, add NCS (1.80 g, 13.5 mmol). Stir and react at 60 °C for 64.5 hours (LCMS detects 15% of the raw materials remaining). Cool the reaction solution to room temperature, add saturated NaHCO3 (50 mL) solution, and extract the mixture with DCM (100 mL * 3). After conventional post - treatment operation two, a residue is obtained. The residue is purified by silica gel column chromatography (EA:PE, EA from 0 to 21.5%) to obtain the white solid compound 278 - E (1.2 g, 4.66 mmol, yield 52%). LC - MS: (ESI) m / z [M + H] + 258.1.

[0229] Step 3: To a solution of 278 - E (300 mg) in MeOH (5 mL), add an aqueous solution of NaOH (70 mg) (2.5 mL). Stir the reaction solution at 50 °C for 2 hours. Concentrate the reaction solution under reduced pressure, add water (5 mL), wash with MTBE (3 mL * 2), adjust the pH to 2 - 3, precipitate a solid, filter, wash the filter cake with water (5 mL * 2), and dry in vacuo to obtain the yellow solid compound 278 - A (200 mg, yield 90%). LCMS: (ESI) m / z. [M + H] + 187.1.

[0230] Referring to the methods of Step 2 and Step 3 in Example 2, start with the following starting materials and carry out two - step reactions to obtain the corresponding final compounds.

[0231]

[0232] The synthesis method of the starting material 283-A involved in the above table is as follows:

[0233]

[0234] Step 1: Dissolve compound 14-c (500 mg, 3.01 mmol, 1 eq) in an aqueous solution of hydrogen bromide (3 mL, 40% content), add paraformaldehyde (130 mg) and a catalytic amount of concentrated sulfuric acid (92 mg, 938 μmol, 50 μL), and stir the reaction at 70 °C for 16 hours. Cool to room temperature, dilute the reaction with water (10 mL), extract with DCM (10 mL * 3), and obtain the crude product after conventional post-treatment operations. The crude product is crushed and slurried in a mixture of PE and DCM (5 / 1) at 25 °C to obtain a brown solid (560 mg), which is a mixture of compounds 283-B and 283-C and is directly used in the next reaction. LC-MS: (ESI) m / z [M + H] + 197.1。

[0235] Step 2: Dissolve the mixture of compounds 283-B and 283-C (560 mg) in MeOH (10 mL), add a methanol solution of sodium methoxide (5.4 M, 2.00 mL), and stir the reaction at 25 °C for 16 hours. Concentrate under reduced pressure, adjust the pH to 4 with 1 M hydrochloric acid, extract with DCM (5 mL * 3), wash the organic phase with saturated NaHCO3 solution (5 mL), and obtain a brown oil 283-D (430 mg) after conventional post-treatment operation 2. The crude product is directly used in the next reaction. LC-MS: (ESI) m / z [M + H] + 211.2。

[0236] Step 3: Add 3-bromo-1-propene (371 mg, 3.07 mmol) to a DMF (5 mL) solution of compound 283-D (430 mg) and K2CO3 (707 mg, 5.11 mmol), and react at 25 °C for 16 hours. After the reaction is completed, add saturated brine (5 mL), extract with EtOAc (3 mL * 3), obtain the crude product after conventional post-treatment operations, and purify the crude product by silica gel column chromatography (EA:PE, EA from 0 to 5.5%) to obtain a brown oil compound 283-A (482 mg, three-step yield 64%). 11H NMR (400 MHz, CDCl3) δ (ppm) 10.29 (s, 1H), 7.71 (s, 1H), 6.12 (ddt, J = 5.3, 10.9, 16.7 Hz, 1H), 5.46 (dd, J = 0.7, 17.2 Hz, 1H), 5.31 (d, J = 10.4 Hz, 1H), 4.50 (s, 2H), 4.48 (d, J = 5.7 Hz, 2H), 3.98 (s, 3H), 3.47 (s, 3H), 2.30 (s, 3H).

[0237] The synthetic method of the starting material 42-A involved in the above table is as follows:

[0238]

[0239] Step 1: To a mixture of 42-B (3 g, 18 mmol) in ACN (30 mL), add 3-bromopropene (2.2 g, 18 mmol) and Na2CO3 (3.8 g, 36 mmol). React at 70 °C for 16 h. After completion of the reaction, the solvent was evaporated to dryness, water (30 mL) was added, and the mixture was extracted with EA (30 mL x 3). After conventional post-treatment operation two, the crude product was obtained, and the crude product was purified by silica gel thin layer chromatography (THF:PE, THF from 0 to 20%) to obtain a yellow solid 42-C (1.3 g, yield 35%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.92 (br s, 1H), 9.98 (s, 1H), 7.41 - 7.51 (m, 1H), 6.50 (s, 1H), 6.06 (m, 1H), 5.27 - 5.48 (m, 2H), 4.59 - 4.74 (m, 2H), 2.51 - 2.55 (m, 2H), 1.12 (t, J = 7.5 Hz, 3H).

[0240] Step 2: To a mixture of 42-C (1.1 g, 5 mmol) in DMF (10 mL), add methyl iodide (1.1 g, 8.00 mmol) and K2CO3 (1.5 g, 10.6 mmol). React at 20 °C for 16 h. Add water (10 mL), and extract with EA (15 mL x 3). After conventional post-treatment operation two, the crude product was obtained, and the crude product was purified by silica gel thin layer chromatography (THF:PE, THF from 0 to 12%) to obtain a white solid 42-A (990 mg, yield 84%). LCMS: (ESI) m / z = 221.2 (M + 1) + .

[0241] The synthetic method of the starting material 47-A involved in the above table is as follows:

[0242]

[0243] Step 1: Referring to the method in Step 1 of Example 2, using 30-A (268 mg, 1.74 mmol) as the raw material, a white solid 47-B (260 mg, yield 77.00%) was obtained by reaction. LCMS: (ESI) m / z = 195.1 (M+1) + .

[0244] Step 2: A mixture of 47-B (1 g, 5.15 mmol), 47-C (1.94 g, 10.3 mmol) and DIEA (2.00 g, 15.5 mmol) in dioxane (12 mL) was reacted at 120 °C for 16 hours. LC-MS showed that ~32.3% of the raw material remained and ~48.0% of the target product was formed. The solvent was evaporated to obtain the crude product, and the crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to obtain a brown oil 47-A (900 mg, yield 48.2%). LCMS: (ESI) m / z = 363.5 (M+1) + .

[0245] Synthesis of Compound 46 in Example 2-a

[0246]

[0247] Step 1: Referring to the method in Step 2 of the synthesis of 47-A, 46-B (1.55 g, 15.45 mmol) was reacted completely with 47-B (1 g, 5.15 mmol), and after work-up, a yellow solid 46-A (528 mg, yield 35.1%) was obtained. LCMS: (ESI) m / z = 275.1 (M+1) + 。

[0248] Steps 2 and 3: Referring to the methods in Steps 2 and 3 of Example 2, starting from 46-A, a two-step reaction was carried out to obtain a white solid compound 46, and the two-step yield was approximately 4.9%. LCMS: (ESI) m / z = 303.0 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.75 - 0.88 (m, 1H) 1.07 (br s, 1H) 1.24 - 1.35 (m, 1H) 2.04 - 2.11 (m, 3H) 2.15 - 2.37 (m, 6H) 2.55 (br s, 3H) 2.70 - 2.80 (m, 2H) 2.83 - 2.91 (m, 2H) 5.58 (s, 1H) 5.92 (d, J = 4.62 Hz, 1H) 6.62 - 6.78 (m, 1H) 7.06 (s, 1H) 8.14 (s, 1H).

[0249] Referring to the synthesis method of Example 2-a, the following starting materials and compound 47-B were used to carry out a three-step reaction to obtain the corresponding final product compound.

[0250]

[0251]

[0252] Synthesis of Compound 55 in Example 2-b

[0253]

[0254] Step 1: Referring to the synthesis method of 31-A, 55-B (1.13 g, 15.45 mmol) was reacted with 47-B (1 g, 5.15 mmol) to obtain 55-A (250 mg, yield 19.63%). 1 H NMR (CDCl3, 400 MHz) δ ppm 10.27 (s, 1H) 7.63 - 7.75 (m, 1H) 6.51 - 6.60 (m, 1H) 6.01 - 6.18 (m, 1H) 5.41 - 5.58 (m, 1H) 5.35 (dd, J = 10.64, 1.47 Hz, 1H) 4.60 - 4.70 (m, 3H) 3.17 (q, J = 7.09 Hz, 4H) 2.23 (s, 3H) 1.07 (t, J = 7.09 Hz, 6H).

[0255] Steps 2 and 3: Referring to the methods of Steps 2 and 3 in Example 2, a two-step reaction was carried out starting from 55-A to obtain the yellow solid compound 55, and the two-step yield was approximately 5.3%. LCMS: (ESI) m / z = 276.2 [M + H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.21 - 9.54 (m, 1H) 6.83 - 7.04 (m, 1H) 6.64 - 6.76 (m, 1H) 5.95 (d, J = 4.84 Hz, 0.201H) 5.76 (s, 0.790H) 2.80 - 2.97 (m, 4H) 2.28 - 2.36 (m, 1H) 2.14 - 2.21 (m, 1H) 2.04 - 2.13 (m, 3H) 1.23 - 1.34 (m, 1H) 0.98 - 1.07 (m, 1H) 0.86 - 0.97 (m, 6H)

[0256] Referring to the synthesis method of Example 2-b, the following starting materials and compound 47-B were used to carry out a three-step reaction to obtain the corresponding final product compound.

[0257]

[0258]

[0259] Synthesis of Compounds 26, 27, 28 and 29 in Example 3-a

[0260]

[0261] Note: Among the four compounds P1, P2, P3, and P4 obtained by chiral resolution in the synthetic route, each corresponds to one of the following four structures, and the absolute configuration has not been assigned yet.

[0262]

[0263] Chiral Resolution of Compound 14-g

[0264] 500 mg of Compound 14-g was resolved by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH₃·H₂O in ETOH]; B%: 10% - 10%) to obtain a colorless oily mixture containing four compounds (130 mg, 473.91 μmol, 26.00% yield) and a mixture containing P3 and P4. The mixture of P3 and P4 was resolved again by SFC (column: REGIS (S,S) WHELK-O1 (250 mm * 25 mm, 10 μm); mobile phase:

[0265] [0.1% NH₃·H₂O in ETOH]; B%: 30% - 30%, 45 min) to obtain Compound P3 and Compound P4.

[0266] White solid compound (P3) (100 mg, 364.55 μmol, 20.00% yield). 1 H NMR (400 MHz, CHLOROFORM-d) Shift 6.97 - 7.09 (m, 1H), 6.47 (s, 1H), 6.02 - 6.17 (m, 1H), 5.84 (d, J = 4.77 Hz, 0.1H), 5.41 - 5.58 (m, 1.9H), 5.32 (dd, J = 1.41, 10.58 Hz, 1H), 4.59 (td, J = 1.50, 4.95 Hz, 2H), 3.82 - 3.93 (m, 3H), 2.63 - 2.72 (m, 0.1H), 2.15 - 2.29 (m, 5H), 1.23 - 1.40 (m, 1.1H), 0.98 - 1.11 (m, 1H), 0.80 - 0.89 (m, 0.1H). (ESI) m / z = 275.3 (M + 1)+, RT = 0.94 min. SFC: RT = 3.227 min.

[0267] White solid compound (P4) (100 mg, 364.55 μmol, 20.00% yield). 1 H NMR (400 MHz, CHLOROFORM-d) Shift 7.05 (s, 1H), 6.47 (s, 1H), 5.98 - 6.20 (m, 1H),, lq 5.84 (d, J = 4.65 Hz, 0.07H), 5.51 (s, 0.93H), 5.46 (qd, J = 1.61, 17.29 Hz, 1H), 5.27 - 5.38 (m, 1H), 4.59 (td, J = 1.54, 4.98 Hz, 2H), 3.85 (s, 3H), 2.11 - 2.30 (m, 5H), 1.22 - 1.40 (m, 1H), 0.97 - 1.13 (m, 1H), 0.78 - 0.91 (m, 0.11H). LCMS: (ESI) m / z = 275.3 (M+1) + , RT = 0.94 min. SFC: RT = 3.751 min.

[0268] 130 mg of a colorless oily mixture containing four compounds was again resolved by SFC, with the conditions (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 um); mobile phase: [CO2 - i - PrOH (0.1% NH3H2O)]; B%: 30% - 30%, min), to obtain compound P1 and a 100 mg mixture containing three compounds P2, P3, and P4.

[0269] White solid compound (P1) (20 mg, 72.91 μmol, 4.0% yield). LCMS: (ESI) m / z = 275.3 (M+1) + , RT = 0.85 min. SFC: RT = 3.28 min.

[0270] 100 mg of a mixture containing three compounds P2, P3, and P4 was subjected to a third SFC resolution, with the conditions (column: REGIS (S,S) WHELK - O1 (250 mm * 25 mm, 10 um); mobile phase: [CO2 - EtOH (0.1% NH3H2O)]; B%: 25% - 25%, 45 min), to obtain compound P2.

[0271] White solid compound (P2) (18 mg, 65.62 μmol, 3.6% yield). LCMS: (ESI) m / z = 275.3 (M+1) + , RT = 1.06 min. SFC: RT = 3.56 min.

[0272] Note: The analytical conditions for the SFC RT results identified in the identification and analysis data of the compounds obtained from the chiral resolution of Compound 14-g are as follows: Column: (S,S)Whelk-01 100×4.6mm I.D., 5.0um; Mobile phase: A: CO2 B: Ethanol(0.05% DEA); Gradient: from 5% to 40% of B in 4.5min and hold 40% for 2min, then 5% of B for 1.5min; Flow rate: 2.5mL / min; Column temperature: 40℃; ABPR: 100bar.

[0273] Synthesis of Compound 28

[0274] Referring to the last step of Synthesis Method 2 of Compound 14, reacting with Compound P3 (90mg, 328.09μmol) gave a pale yellow solid 28 (50mg, 209.18μmol, 63.76% yield). 1 H NMR(400MHz, DMSO-d6) Shift 9.28 - 9.63(m, 1H), 6.79 - 6.98(m, 1H), 6.45 - 6.55(m, 1H), 5.73(d, J=4.52Hz, 0.2H), 5.39(s, 0.8H), 3.66 - 3.80(m, 3H), 2.12 - 2.29(m, 1.8H), 2.05(s, 3H), 1.21 - 1.36(m, 1H), 1.07(td, J=4.39, 7.61Hz, 0.2H), 0.96(q, J=4.28Hz, 0.8H), 0.71(br d, J=3.42Hz, 0.2H). LCMS:(ESI) m / z=235.2(M+1) + , RT=0.76min.

[0275] Synthesis of Compound 29

[0276] Referring to the last step of Synthesis Method 2 of Compound 14, reacting with Compound P4 (90mg, 328.09μmol) gave a pale yellow solid 29 (60mg, 251.02μmol, 76.51% yield). LCMS:(ESI) m / z=235.2(M+1) + , RT=0.76min. 11H NMR (400 MHz, DMSO-d6) Shift 9.26 - 9.66 (m, 1H), 6.77 - 7.03 (m, 1H), 6.45 - 6.62 (m, 1H), 5.73 (d, J = 4.65 Hz, 0.2H), 5.39 (s, 0.8H), 3.62 - 3.83 (m, 3H), 2.10 - 2.28 (m, 1.8H), 2.05 (s, 3H), 1.14 - 1.34 (m, 0.2H), 0.96 (q, J = 4.24 Hz, 0.8H), 0.65 - 0.76 (m, 0.2H).

[0277] Synthesis of Compound 26

[0278] Referring to the last step of the second synthetic method of Compound 14, react with Compound P1 (18 mg, 65.62 μmol), and then separate by preparative HPLC (column: Boston Prime C18 150 * 30 mm * 5 μm; mobile phase: [water (FA) - ACN]; B%: 23% - 43%, 16 min) to obtain white solid 26 (8 mg, 34.15 μmol, 52.05% yield). LCMS: (ESI) m / z = 235.2 (M + 1)+, RT = 0.890 min. 1 1H NMR (400 MHz, DMSO-d6) Shift 9.23 - 9.72 (m, 1H), 6.74 - 7.07 (m, 1H), 6.40 - 6.63 (m, 1H), 5.73 (d, J = 4.65 Hz, 1H), 5.39 (s, 1H), 3.60 - 3.80 (m, 3H), 2.13 - 2.28 (m, 2H), 2.05 (s, 3H), 1.02 - 1.36 (m, 1H), 0.66 - 1.00 (m, 1H).

[0279] Synthesis of Compound 27

[0280] Referring to the last step of the second synthetic method of Compound 14, react with Compound P2 (18 mg, 65.62 μmol), and then separate by preparative HPLC (column: Boston Prime C18 150 * 30 mm * 5 μm; mobile phase: [water (HCl) - ACN]; B%: 25% - 45%, 16 min) to obtain light yellow solid 27 (5 mg, 19.64 μmol, 29.93% yield). LCMS: (ESI) m / z = 235.2 (M + 1) + , RT = 0.838 min. 11H NMR (400 MHz, DMSO-d6) Shift 9.29 - 9.64 (s, 1H), 6.78 - 7.00 (s, 1H), 6.40 - 6.57 (s, 1H), 5.73 (d, J = 4.52 Hz, 0.2H), 5.39 (s, 0.8H), 3.70 - 3.77 (s, 3H), 2.11 - 2.26 (m, 1.8H), 2.05 (s, 3H), 1.23 - 1.34 (m, 1.2H), 1.07 (dt, J = 4.46, 8.28 Hz, 0.2H), 0.96 (q, J = 4.28 Hz, 0.8H), 0.88 (br d, J = 5.14 Hz, 0.2H), 0.68 - 0.74 (m, 0.2H).

[0281] Synthesis of Compounds 268 and 269 in Example 3-b

[0282]

[0283] Note: The two compounds d1 and d2 obtained by chiral resolution in the synthetic route correspond to one of the following two structures respectively, and the absolute configuration has not been assigned yet.

[0284]

[0285] Chiral Resolution of Compound 14-g

[0286] 10 g of Compound 14-g was resolved by SFC (column: REGIS (s, s) WHELK-O1 (250 mm × 50 mm, 10 μm); mobile phase: [CO2 - EtOH (0.1% NH3H2O)]; B%: 25%, isocratic elution mode; column temperature: 35 °C; flow rate: 200 mL / min) to obtain off-white solid Compound d3 (0.9 g, 3.28 mmol, 9.00% yield) and off-white solid Compound d2 (1.1 g, 4.01 mmol, 11.00% yield).

[0287] Compound d3, (ESI) m / z = 275.1 (M + 1) + , RT = 1.426 min. SFC: RT = 3.217 min, ~19.1% and RT = 3.547 min, ~80.9%. 11H NMR (400 MHz, DMSO-d6) δ 6.91 (s, 1H), 6.66 - 6.73 (m, 1H), 5.98 - 6.17 (m, 1H), 5.77 (d, J = 4.65 Hz, 1H), 5.37 - 5.55 (m, 1H), 5.28 (dd, J = 1.41, 10.58 Hz, 1H), 4.56 - 4.70 (m, 2H), 3.79 - 3.89 (m, 3H), 2.57 (qd, J = 4.92, 7.50 Hz, 1H), 2.14 - 2.30 (m, 1H), 2.10 (s, 3H), 1.02 - 1.10 (m, 1H), 0.65 - 1.01 (m, 1H).

[0288] Compound d2, (ESI) m / z = 275.1 (M+1) + , RT = 1.423 min. SFC: RT = 3.264 min, ~63.3% and RT = 3.745 min, ~36.7%. 1 1H NMR (400 MHz, DMSO-d6) δ 6.87 - 7.04 (m, 1H), 6.68 (d, J = 4.28 Hz, 1H), 6.01 - 6.17 (m, 1H), 5.76 (d, J = 4.52 Hz, 1H), 5.37 - 5.52 (m, 2H), 5.27 (td, J = 1.50, 10.58 Hz, 1H), 4.48 - 4.77 (m, 2H), 3.82 (d, J = 8.80 Hz, 3H), 2.57 (qd, J = 4.89, 7.60 Hz, 1H), 2.14 - 2.27 (m, 2H), 2.10 (d, J = 2.20 Hz, 3H), 1.03 - 1.31 (m, 1H), 0.66 - 1.01 (m, 1H).

[0289] Note, the analytical conditions for the SFC RT results identified in the identification and analysis data of the compound obtained by chiral resolution of compound 14 - g are: column: (S,S) Whelk - 01 100×4.6 mm I.D., 5.0 um; mobile phase: A: CO2 B: Ethanol (0.05% DEA); gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2 min, then 5% of B for 1.5 min; flow rate: 2.5 mL / min; column temperature: 40 °C; ABPR: 100 bar.

[0290] Synthesis of compound 268

[0291] Referring to the last step of Synthetic Method 2 of Reference Compound 14, reacting with Compound d3 (850 mg, 3.10 mmol) gave white solid 268 (315 mg, 1.34 mmol, 43.4% yield). LCMS: (ESI) m / z = 235.0 (M+1) + , RT = 1.062 min. SFC: RT = 3.790 min, 74.64% and RT = 4.125 min, 25.28%. 1 H NMR (400 MHz, DMSO-d6) δ 9.25 - 9.73 (m, 1H), 6.75 - 7.04 (m, 1H), 6.33 - 6.61 (m, 1H), 5.29 - 5.81 (m, 1H), 3.64 - 3.79 (m, 3H), 2.12 - 2.26 (m, 2H), 2.04 (s, 3H), 1.28 (dt, J = 4.52, 8.07 Hz, 1H), 0.95 (q, J = 3.95 Hz, 1H).

[0292] Synthesis of Compound 269

[0293] Referring to the last step of Synthetic Method 2 of Reference Compound 14, reacting with Compound d2 (18 mg, 52.5 μmol) gave white solid 269 (8 mg, 34.15 μmol, 52.05% yield). LCMS: (ESI) m / z = 235.2 (M+1) + , RT = 0.890 min. 1 H NMR (400 MHz, DMSO-d6) 9.23 - 9.72 (m, 1H), 6.74 - 7.07 (m, 1H), 6.40 - 6.63 (m, 1H), 5.73 (d, J = 4.65 Hz, 1H), 5.39 (s, 1H), 3.60 - 3.80 (m, 3H), 2.13 - 2.28 (m, 2H), 2.05 (s, 3H), 1.02 - 1.36 (m, 1H), 0.66 - 1.00 (m, 1H). SFC: RT = 3.966 min, 20.82% and RT = 4.278 min, 79.98%.

[0294] Note: The SFC analysis conditions for the RT results identified in the synthesis of compounds 268 and 269 are as follows: Column: Chiralpak AD-3 150*4.6mm I.D., 3um; Mobile phase: A: CO2, B: iso-propanol (0.05% DEA); Gradient: from 5% to 40% of B in 4min and hold 40% for 2min, then 5% of B for 2min; Flow rate: 2.5mL / min; Column temperature: 35°C; ABPR: 1500Psi

[0295] Synthesis of Compound 2 in Example 4

[0296]

[0297] Step 1: At -78°C, add a THF solution of n-butyllithium (0.71 mL, 2.4 mol / L, 0.85 mmol) to a THF (10 mL) solution of Compound 2-A (250 mg), and stir the reaction under nitrogen protection for 0.5 hour. Subsequently, add Compound 2-B (172 mg, 1.48 mmol), and continue to stir the reaction at -78°C for 3 hours. After the reaction is completed, quench the reaction with water (20 mL), and extract with EA (25 mL × 3). After conventional post-treatment operations, a crude product of yellow oil 2-C (90 mg) is obtained. LC-MS: (ESI) m / z [M+H] + 343.1.

[0298] Step 2: At -78°C, add tetrabutylammonium fluoride (244 mg, 0.93 mmol) to a THF (10 mL) solution of Compound 2-C (90 mg, crude product). Stir the reaction at 25°C for 1 hour. After the reaction is completed, quench the reaction with water (10 mL), and extract with EA (20 mL × 3). After conventional post-treatment operations, purify by silica gel column chromatography (EA:PE = 0 to 10%:90%) to obtain yellow solid Compound 2 (60 mg). 1 HNMR (400 MHz, DMSO-d6) δ 8.19–8.06 (m, 2H), 7.56–7.43 (m, 3H), 7.22–7.18 (m, 1H), 6.89–6.87 (m, 1H), 6.16–6.11 (m, 1H), 3.30–3.27 (m, 4H). LC-MS: (ESI) m / z [M+H] + 229.7.

[0299] Synthesis of Compound 1 in Example 4-a

[0300]

[0301] Step 1: Referring to the method in Step 1 of Example 4, reacting with compound 1-A (400 mg, 1.7 mmol) to obtain compound 1-B (160 mg, yield 36%). LC-MS: (ESI) m / z [M+H] + 262.

[0302] Step 2: Stirring and reacting the solution of compound 1-B (180 mg, 0.68 mmol) in TFA (1.02 mL) and DCM (15 mL) at room temperature for 2 hours. Concentrating under reduced pressure and purifying by silica gel column chromatography (EA:PE, EA from 0 to 25%) to obtain white solid compound 1-C (122 mg, yield 73%). LC-MS: (ESI) m / z [M+H] + 244.1.

[0303] Step 3: At -10 °C, adding boron tribromide (2M DCM solution, 1.25 mL) to the DCM (10 mL) solution of compound 1-C (122 mg, 0.5 mmol). Reacting at -10 °C for 2 hours. After completion of the reaction, diluting with EA (30 mL) and washing with saturated NaHCO3 solution (15 mL x 2). After conventional post-treatment operation two, purifying by prep HPLC (column: YMC-Actus Triart C18 20*250 mm, 5 um, phase A: H2O (0.1% FA), phase B: ACN, 10% - 95%) to obtain yellow solid compound 1 (51.4 mg, yield 44%). LC-MS (ESI) m / z: 230.1 (M+H) + ; 1 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 10.66 (s, 1H), 8.90 (dd, J = 4.2, 1.8 Hz, 1H), 8.55 (dd, J = 8.4, 1.8 Hz, 1H), 8.15 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.55 - 7.49 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.42 (t, J = 7.2 Hz, 1H), 2.81 - 2.58 (m, 3H), 2.26 - 2.14 (m, 1H).

[0304] Synthesis of Compound 287 of Example 4-b

[0305]

[0306] Step 1: At -78 °C, add a THF solution of n-butyllithium (1.6 M hexane solution, 1.53 mL, 2.45 mmol) to a THF (5 mL) solution of compound 287-A (400 mg, 1.63 mmol), and stir the reaction under nitrogen protection for 0.5 h. Subsequently, add compound 2-B (1.96 mmol), and continue to stir the reaction at -78 °C for 3 h. After completion of the reaction, quench the reaction with saturated ammonium chloride solution (10 mL), and extract with EA (15 mL × 3). After conventional post-treatment operation two, purify by silica gel column chromatography (EA:PE, EA from 0 to 16%) to obtain yellow solid compound 287-B (165 mg, yield 40.4%). LC-MS: (ESI) m / z [M+H] + 251.1.

[0307] Step 2: Refer to the method of Step 3 in Example 4-a, and react with compound 287-B (160 mg) to obtain yellow solid compound 1 (7.1 mg, yield 4.7%). LC-MS: (ESI) m / z: 237 (M+H) + ; 1 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.28 (s, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.57 (t, J = 7.5 Hz, 1H), 4.29 - 4.20 (m, 4H), 2.70 - 2.52 (m, 2H), 2.48 - 2.41 (m, 1H), 2.20 - 2.08 (m, 1H).

[0308] Synthesis of Compounds 3, 112, and 107 in Example 5

[0309]

[0310] Step 1: At 20 °C, add aluminum trichloride (6.98 g, 52.32 mmol) to a DCM (125 mL) solution of compound 3-A (5.0 g, 23.78 mmol), stir for 10 minutes, then add compound 3-B (3.57 g, 35.68 mmol) in one portion, and stir the reaction at 20 °C for 30 minutes. Distill off the solvent under reduced pressure, dilute the residue with water (100 mL), adjust the pH to 1 - 2 with 1 M HCl, and extract with EA (100 mL × 3). After conventional post-treatment operation two, purify by silica gel column chromatography (EA:PE = 0 to 70%:30%) to obtain yellow solid compound 3-C (1.5 g, 4.59 mmol, yield 19.31%). LCMS: (ESI) m / z = 310.9 (M+1) +1 . 1HNMR(400MHz, DMSO-d6) Shift 12.02(br s, 1H), 10.42(s, 1H), 7.50(s, 1H), 6.54(s, 1H), 3.83(s, 3H), 3.57(s, 3H), 3.08(t, J=6.40Hz, 2H), 2.70 - 2.79(m, 2H), 2.52 - 2.55(m, 2H), 2.45 - 2.49(m, 2H).

[0311] Step 2 (Representative operation for constructing a five - membered lactone ring): To a mixture of compound 3 - C (800 mg, 2.58 mmol) in water (30 mL), add NaOH (309.38 mg, 7.73 mmol) and NaBH4 (292.60 mg, 7.73 mmol). Stir the reaction at 20 °C for 60 hours. Adjust the pH to 1 - 2 with 2 M HCl, a white solid precipitates, and the mixture is extracted with EA (100 mL×3). After conventional post - treatment operations, the residue obtained is slurried with EA (10 mL), filtered, and washed with EA (3 mL×2) to obtain white solid compound 3 (520 mg, 1.76 mmol, yield 68.37%). LCMS: (ESI) m / z=280.9(M + 1) + ; 1 HNMR(400MHz, DMSO-d6) Shift 12.04(br s, 1H), 9.61(br s, 1H), 7.00(s, 1H), 6.48(s, 1H), 5.59(t, J=7.53Hz, 1H), 3.72(s, 3H), 2.66 - 2.72(m, 2H), 2.62(t, J=9.41Hz, 1H), 2.53 - 2.59(m, 1H), 2.40 - 2.46(m, 3H), 2.03 - 2.15(m, 1H).

[0312] Step 3: Stir a solution of compound 3 (100 mg, 0.36 mmol) in DCM (3.0 mL) and TFA (0.5 mL) at 20 °C for 16 hours. Concentrate the solution under reduced pressure to remove the solvent, and purify the resulting residue by silica gel column chromatography (EA:PE = 0 to 5%:95%) to obtain white solid compound 112 (77 mg, 0.28 mmol, yield 78.17%). LCMS: (ESI) m / z=263.1(M + 1) + , 285.1(M + Na) + ; 11H NMR (400 MHz, CHLOROFORM-d) Shift 7.17 (s, 1H), 6.63 (s, 1H), 5.73 (t, J=7.03 Hz, 1H), 3.85 (s, 3H), 2.92 - 3.03 (m, 2H), 2.78 - 2.85 (m, 2H), 2.68 - 2.77 (m, 1H), 2.61 - 2.67 (m, 2H), 2.04 - 2.17 (m, 1H).

[0313] Step 4: A solution of compound 112 (70 mg, 0.27 mmol) in MeOH (2 mL) was stirred at 50 °C for 16 h. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE = 0 to 35%:65%) to obtain white solid compound 107 (35 mg, 0.11 mmol, yield 42.33%). LCMS: (ESI) m / z = 294.9 (M+1) + ; 1 1H NMR (400 MHz, CHLOROFORM-d) Shift 7.90 (s, 1H), 7.01 (s, 1H), 6.52 (s, 1H), 5.63 - 5.74 (m, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 2.78 - 2.91 (m, 2H), 2.70 - 2.77 (m, 2H), 2.59 - 2.69 (m, 3H), 2.06 - 2.19 (m, 1H).

[0314]

[0315] A solution of compound 112 (70 mg, 0.27 mmol) in EtOH (2 mL) was stirred at 50 °C for 16 h. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE = 0 to 35%:65%) to obtain white solid compound 108 (25 mg, 0.077 mmol, yield 28.86%). LCMS: (ESI) m / z = 308.9 (M+1) + , 330.9 (M+Na) + ; 1 1H NMR (400 MHz, CHLOROFORM-d) Shift 8.04 (s, 1H), 7.01 (s, 1H), 6.52 (s, 1H), 5.65 - 5.72 (m, 1H), 4.17 (q, J = 7.03 Hz, 2H), 3.80 (s, 3H), 2.79 - 2.87 (m, 2H), 2.69 - 2.74 (m, 2H), 2.59 - 2.68 (m, 3H), 2.06 - 2.19 (m, 1H), 1.27 (t, J = 7.15 Hz, 3H).

[0316] Synthesis of Compound 109 in Example 5-a

[0317]

[0318] To a solution of Compound 112 (60 mg, 0.23 mmol) in DMF (2 mL) was added a solution of dimethylamine in THF (2 M, 114.39 μL). The reaction was stirred at 20 °C for 16 hours. LCMS showed that only a small amount of the starting material (3%) remained unreacted. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 60%) to obtain white solid Compound 109 (30 mg, yield 41%). LCMS: (ESI) m / z = 308.2 (M+1) + , 1 1H NMR (400 MHz, DMSO-d6) Shift 9.72 (s, 1H), 7.00 (s, 1H), 6.47 (s, 1H), 5.59 (t, J = 7.65 Hz, 1H), 3.72 (s, 3H), 2.93 (s, 3H), 2.81 (s, 3H), 2.60 - 2.72 (m, 3H), 2.52 - 2.59 (m, 2H), 2.39 - 2.50 (m, 2H), 2.02 - 2.19 (m, 1H)

[0319] Referring to the synthesis method of Example 5-a, the following starting materials were reacted with Compound 112 to obtain the corresponding final products.

[0320]

[0321]

[0322] Referring to the synthesis method of Example 5-a, the following starting materials were reacted to obtain the corresponding final products.

[0323]

[0324]

[0325] Synthesis of Compound 130 in Example 5-b

[0326]

[0327] Step 1: To an aqueous solution (16 mL) of NaHCO3 (646 mg, 7.69 mmol) containing compound 130-B (1.57 g, 7.69 mmol), add compound 130-A (3.70 g, 23.1 mmol). Periodically add NaHCO3 (2.26 g, 26.9 mmol, 1.05 mL of aqueous solution) to maintain the pH at 7.5. Stir at 20 °C for 16 h. Add phosphoric acid (5 mL) to adjust the pH to 4 - 5, and extract with EtOAc (15 mL × 3). The organic phase is cooled to 0 °C to precipitate a solid, which is then filtered. The crude product is recrystallized from EtOAc (4 mL) to obtain white solid compound 130-C (2.1 g, yield 83%). 1 H NMR (400 MHz, DMSO-d6) Shift = 12.50 (br s, 1H), 7.88 (brt, J = 5.4 Hz, 1H), 6.91 (br d, J = 8.0 Hz, 1H), 4.08 - 3.94 (m, 1H), 3.45 - 3.24 (m, 2H), 2.00 - 1.86 (m, 2H), 1.62 (br d, J = 10.0 Hz, 6H), 1.38 (s, 8H), 1.34 (br s, 1H), 1.26 - 1.09 (m, 3H), 0.97 - 0.77 (m, 2H).

[0328] Step 2: To a solution of compound 130-C (120 mg, 365 μmol) in DMF (2 mL), add cyclohexylamine (43.5 mg, 438 μmol), DIEA (142 mg, 1.10 mmol), and HATU (166 mg, 438 μmol). Stir at 20 °C for 2 h. Dilute with water (20 mL) and extract with EtOAc (10 mL × 3). After the conventional post-treatment operation II, the crude product is obtained. The crude product is crushed and slurried in EtOAc at 20 °C for 3 h. Filter to obtain white solid compound 130-D (100 mg, yield 66.82%). 1 H NMR (400 MHz, DMSO-d6) Shift = 7.84 - 7.71 (m, 1H), 7.61 (br d, J = 7.8 Hz, 1H), 6.65 (br d, J = 8.0 Hz, 1H), 4.02 - 3.89 (m, 1H), 3.49 (br d, J = 7.3 Hz, 1H), 3.33 - 3.26 (m, 1H), 3.24 - 3.13 (m, 1H), 1.92 (br d, J = 6.8 Hz, 2H), 1.63 (br d, J = 10.8 Hz, 10H), 1.38 (s, 9H), 1.30 - 1.03 (m, 9H), 0.95 - 0.76 (m, 2H).

[0329] Step 3: Add a dioxane solution of HCl (2 M, 1 mL) to a mixture of Compound 130-D (100 mg, 244 μmol) in dioxane (1 mL). Stir at 20 °C for 3 hours. Concentrate under reduced pressure to obtain the white solid Compound 130-E (90.0 mg, HCl salt), and the crude product is directly used in the next reaction.

[0330] Step 4: Add TEA (40.8 mg, 0.4 mmol) and 112 (35.3 mg, 0.134 mmol) to a solution of Compound 130-E (50 mg, 0.134 mmol, HCl salt) in DMF (1 mL), and stir at 40 °C for 16 hours. Concentrate under reduced pressure to remove the solvent, and purify the resulting residue by prep HPLC (FA method - B; B%: 35% - 55%, 10 min) to obtain the white solid Compound 130 (25 mg, yield 29.32%). LCMS: (ESI) m / z = 572.3 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) Shift = 9.61 (br s, 1H), 7.85 (dd, J = 2.4, 8.2 Hz, 1H), 7.68 (br d, J = 6.8 Hz, 2H), 6.99 (d, J = 2.5 Hz, 1H), 6.48 (s, 1H), 5.59 (t, J = 7.5 Hz, 1H), 4.30 (q, J = 7.1 Hz, 1H), 3.72 (s, 3H), 3.55 - 3.44 (m, 1H), 3.29 - 3.17 (m, 2H), 2.71 - 2.62 (m, 3H), 2.38 - 2.31 (m, 2H), 2.17 - 2.02 (m, 1H), 1.91 (br d, J = 5.3 Hz, 2H), 1.78 - 1.45 (m, 12H), 1.32 - 0.99 (m, 9H), 0.85 (br d, J = 10.0 Hz, 2H)

[0331] Referring to the methods of Steps 2, 3, and 4 in the synthesis method of Example 5-b, replace cyclohexylamine with the following starting materials in Step 2, and perform three-step reactions to obtain the corresponding final product compounds.

[0332]

[0333] Synthesis of Compound 111 in Example 6

[0334]

[0335] At 20 °C, triphenylphosphine (93.58 mg, 356.80 μmol) and di-tert-butyl azodicarboxylate (DBAD, 61.62 mg, 0.27 mmol) were added to a solution of compound 3 (50 mg, 0.18 mmol) and isopropanol (10.72 mg, 0.18 mmol) in THF (2 mL). The reaction was stirred at 20 °C for 16 hours. The solvent was removed by distillation under reduced pressure. The residue was purified first by silica gel column chromatography (EA:PE = 0 to 40%:60%) and then by preparative HPLC (FA method - A, B%: 33% - 53%, 10 min) to obtain white solid compound 111 (20 mg, 0.06 mmol, yield 33.74%). LCMS: (ESI) m / z = 322.9 (M+1) + ; 1 HNMR (400 MHz, CHLOROFORM-d) Shift 8.17 (s, 1H), 7.00 (s, 1H), 6.52 (s, 1H), 5.64 - 5.74 (m, 1H), 5.04 (quin, J = 6.21 Hz, 1H), 3.80 (s, 3H), 2.75 - 2.89 (m, 2H), 2.59 - 2.72 (m, 5H), 2.09 - 2.20 (m, 1H), 1.24 (dd, J = 2.26, 6.27 Hz, 6H).

[0336] Referring to the synthesis method of compound 111, the starting materials in the following table were reacted with compound 3 to obtain the corresponding final product compounds.

[0337]

[0338] Synthesis of compound 4 in Example 7

[0339]

[0340] Step 1: At 0 °C, lithium aluminum hydride (360 mg, 9.49 mmol) was added to a solution of compound 4-A (3.00 g, 11.8 mmol) in THF (60 mL). The reaction was stirred at 0 °C for 1 hour. The reaction was quenched with 1 M hydrochloric acid solution, and water (30 mL) was added. The mixture was extracted with EA. After conventional post-treatment operations, purple solid compound 4-B (2.55 g, 9.57 mmol, yield 82%) was obtained. 1 HNMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 6.51 (s, 1H), 3.86 (s, 3H), 3.68 - 3.66 (t, J = 4, 2H), 2.73 - 2.70 (t, J = 4, 2H), 1.89 - 1.83 (m, 2H).

[0341] Step 2: Add DHP (2.05 g, 24.4 mmol) and pyridinium p-toluenesulfonate (PPTS, 245 mg, 976 μmol) to a solution of compound 4-B (2.55 g, 9.77 mmol) in DCM (50 mL). Stir the reaction at room temperature for 16 h, add water, and extract the mixture with DCM (20 mL × 3). After conventional post-treatment operation 2, purify by silica gel column chromatography (EA:PE, EA from 0 to 11.5%) to obtain yellow oil 4-C (3.3 g, 6.15 mmol, purity 80%). LCMS: (ESI) m / z = 453.1 (M+Na) + .

[0342] Step 3: Ensure that the glassware used in this operation is dry and anhydrous. At -78 °C, add a solution of n-butyllithium in THF (2.5 M, 2.5 mL) to a solution of compound 4-C (2.00 g, purity 80%) in THF (50 mL). After stirring for 1 h, add succinic anhydride (932 mg, 9.32 mmol), and continue stirring the reaction for 2 h. Quench the reaction by adding 10% citric acid solution (30 mL), and extract the mixture with EA (30 mL × 3). After conventional post-treatment operation 2, purify by silica gel column chromatography (THF:PE, THF from 0 to 40%) to obtain colorless oil 4-C (0.65 g, 1.3 mmol, LCMS purity 89.9%). LCMS: (ESI) m / z = 473.2 (M+Na) + . 1 HNMR shows that there are 2 molecules of succinic anhydride remaining.

[0343] Step 4: Add NaBH4 (75.70 mg, 2.00 mmol) to a mixture of compound 4-D (601 mg, purity 89.9%) in an aqueous solution of NaOH (190 mg, 4.75 mmol) (5.5 mL). Stir the reaction at 25 °C for 16 h, carefully add 10% citric acid solution (30 mL) to adjust the pH to 2, and extract the mixture with EA (20 mL × 3). After conventional post-treatment operation 2, 508 mg of light yellow gum is obtained. LCMS shows that the product is a mixture of 20.3% of compound 4-F [(ESI) m / z = 457.4 (M+Na) + and 54.8% of compound 4-E [(ESI) m / z = 475.1 (M+Na) + .

[0344] Step 5: To a solution of the mixture of Compound 4-E and 4-F (190 mg) in THF (2 mL) and water (1 mL) was added p-toluenesulfonic acid monohydrate (40 mg, 210.28 μmol). The reaction was stirred at 25 °C for 16 hours. The off-white solid Compound 4 (35 mg, 122.24 μmol) was isolated by Prep HPLC (FA method - A, B%: 15% - 35%, 10 min). LCMS: (ESI) m / z = 267.1 (M + 1) + ; 1 HNMR (400 MHz, CHLOROFORM-d) Shift = 7.02 (s, 1H), 6.49 (s, 1H), 5.74 - 5.67 (m, 1H), 3.81 (s, 3H), 3.74 - 3.63 (m, 2H), 2.81 - 2.70 (m, 2H), 2.69 - 2.59 (m, 3H), 2.22 - 2.11 (m, 1H), 1.91 - 1.83 (m, 2H).

[0345] Synthesis of Compounds 5 and 6 in Example 8-a

[0346]

[0347] Step 1: Under nitrogen protection, a suspension of sodium hydride (304 mg, 7.61 mmol, purity 60%) in DMSO (20 mL) was heated at 65 °C for one hour. After cooling to room temperature, THF (20 mL) was added to the clear reaction solution. The reaction solution was cooled to -15 °C, and a solution of trimethylsulfonium iodide (1.41 g, 6.92 mmol) in DMSO (20 mL) was added dropwise. After 3 minutes, a solution of Compound 6-A (2 g, 6.92 mmol) in THF (20 mL) was added dropwise. The reaction was stirred at 25 °C for 2 hours. Under the condition of 0 - 10 °C, the reaction solution was quenched with saturated NH4Cl (50 mL) solution, diluted with 100 mL of water, and the mixture was extracted with EA (100 mL × 2). After conventional post-treatment operation two, a yellow gummy product Compound 6-B (2 g, crude product) was obtained, and the crude product was directly used in the next step of the reaction.

[0348] Step 2: A yellow mixture of Compound 6-B (2 g, crude product), (1-methoxy-2-methyl-prop-1-enyloxy)-trimethylsilane (5.75 g, 33 mmol), and tetrabutylammonium fluoride trihydrate (1.04 g, 3.30 mmol) was stirred at 60 °C for 12 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (EA: PE, EA from 0 to 3%) to obtain a yellow gummy product Compound 6-C (920 mg, 2.46 mmol, two-step yield approximately 32%). 11H NMR (400 MHz, CDCl3) δ (ppm) 7.53 (s, 1H), 6.82 (s, 1H), 5.61 (dd, J = 6.5, 9.5 Hz, 1H), 5.29 - 5.34 (m, 2H), 3.85 (s, 3H), 3.78 - 3.83 (m, 2H), 2.52 (dd, J = 6.4, 12.9 Hz, 1H), 1.99 (dd, J = 9.8, 12.8 Hz, 1H), 1.38 (s, 3H), 1.32 (s, 3H), 1.26 (t, J = 7.03 Hz, 3H).

[0349] Step 3: Dissolve compound 6-C (760 mg, 2.04 mmol) and methyl prop-2-enoate (438 mg, 5.09 mmol) in 5 mL of anhydrous toluene, add cesium carbonate (995 mg, 3.05 mmol), triphenylphosphine (427 mg, 1.63 mmol) and palladium acetate (183 mg, 814 mmol). Deoxygenate the mixture under reduced pressure, displace with nitrogen, and stir at 80 °C for 12 h under a nitrogen atmosphere. Cool the reaction solution to room temperature, dilute with 30 mL of water, and extract the mixture with EA (30 mL × 2). After conventional post-treatment operations, a residue is obtained. The residue is purified by silica gel column chromatography (EA:PE, EA from 0 to 15%) to obtain the white gummy product compound 6-D (560 mg, 1.48 mmol, yield 72.68%). 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.95 - 8.01 (m, 1H), 7.55 (s, 1H), 6.81 (s, 1H), 6.39 - 6.47 (m, 1H), 5.63 (dd, J = 6.5, 9.5 Hz, 1H), 5.33 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.78 (d, J = 7.03 Hz, 2H), 2.53 (dd, J = 6.5, 12.8 Hz, 1H), 2.02 (dd, J = 9.8, 12.8 Hz, 1H), 1.39 (s, 3H), 1.33 (s, 3H), 1.23 - 1.27 (m, 3H).

[0350] Step 4: Refer to the method of the representative operation of catalytic hydrogenation. Using compound 6-D (528 μmol) as the raw material, react to obtain the yellow gummy substance 6-E (342 μmol, 64.66% yield). Purify by silica gel column chromatography (EA:PE, EA from 0 to 15%). 11H NMR (400 MHz, CDCl3) δ (ppm) 7.13 (s, 1H), 6.77 (s, 1H), 5.64 (dd, J = 6.4, 9.6 Hz, 1H), 5.27 (s, 2H), 3.83 (s, 3H), 3.72 - 3.81 (m, 2H), 3.69 (s, 3H), 2.86 - 2.94 (m, 2H), 2.55 - 2.62 (m, 2H), 2.48 (dd, J = 6.5, 12.8 Hz, 1H), 1.99 - 2.05 (m, 1H), 1.37 (s, 3H), 1.32 (s, 3H), 1.23 - 1.28 (m, 3H).

[0351] Step 5: 6-E (130 mg, 342 μmol) was stirred in a reaction solution of DCM (1.5 mL) and TFA (0.1 mL) at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to dryness to obtain a pink gummy product, compound 6-F (130 mg, crude product), which was directly used in the next step. LC-MS: (ESI) m / z. [M+H] + 290.9.

[0352] Step 6: 6-F (130 mg) was dissolved in MeOH (1 mL), and an aqueous NaOH solution (238 mg, 895 μmol) was added. The reaction solution was stirred at 25 °C for 30 minutes. The pH of the reaction solution was adjusted to 3 with 1 M HCl solution and stirred at 25 °C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 10 mL of water. The mixture was extracted with EA (10 mL × 2). After conventional post-treatment operations, a residue was obtained. The residue was purified by silica gel column chromatography to obtain a white solid, compound 5 (60 mg, 186 μmol, two-step yield 54.4%). LC-MS: (ESI) m / z. [M+H] + 323.1。 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.65 (s, 1H), 7.02 (s, 1H), 6.48 (s, 1H), 5.58 (dd, J = 6.5, 9.8 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 3H), 3.34 (s, 2H), 2.67 - 2.75 (m, 2H), 2.30 - 2.37 (m, 1H), 2.08 (dd, J = 10.0, 12.5 Hz, 1H), 1.25 (s, 3H), 1.21 (s, 3H).

[0353] Step 7: Dissolve 5 (18 mg) in MeOH (10 mL), add NaOH aqueous solution (1 M, 111 μL), and stir the reaction solution at 40 °C for 60 h. LCMS shows that 18% of the starting material remains, and 30% of the target product is formed. The reaction solution is concentrated under reduced pressure, EA and water (5 mL) are added, the pH is adjusted to 3 with 1 M HCl solution, and the mixture is extracted with EA (5 mL × 2). After conventional post-treatment operations, a residue is obtained. The residue is purified by prep-HPLC (column: YMC Triart C18 150*25 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-50%, 10 min) to obtain a white solid compound 6 (2 mg, 6.16 μmol, yield 11%). LCMS: ESI) m / z = 309.2 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) Shift = 12.03 (br s, 1H), 9.62 (br s, 1H), 7.03 (s, 1H), 6.47 (s, 1H), 5.57 (dd, J = 6.5, 10.0 Hz, 1H), 3.71 (s, 3H), 2.68 (t, J = 7.7 Hz, 2H), 2.42 (t, J = 7.7 Hz, 2H), 2.31 (dd, J = 6.4, 12.7 Hz, 1H), 2.12 - 2.05 (m, 1H), 1.24 (s, 3H), 1.20 (s, 3H).

[0354] Synthesis of Compounds 7 and 8 in Example 8-b

[0355]

[0356] Steps 1 and 2: Referring to the methods of Steps 1 and 2 in Example 5, using compound 7-A as the starting material, a white solid compound 7 is obtained through two-step reactions with a two-step yield of approximately 2.4%. LCMS: (ESI) m / z = 288.6 (M+1) + ; 1 1H NMR (400 MHz, DMSO-d6) Shift 10.44 (s, 1H), 7.36 (s, 1H), 6.63 (s, 1H), 5.59 (t, J = 7.65 Hz, 1H), 3.76 (s, 3H), 2.53 - 2.70 (m, 2H), 2.41 - 2.50 (m, 1H), 1.98 - 2.18 (m, 1H).

[0357] Step 3: Add K2CO3 (317.72 mg, 2.30 mmol) to a solution of compound 7 (220 mg, 766.27 umol) and chloromethyl ethyl ether (86.93 mg, 919.52 umol) in acetone (8 mL), and stir at 20 °C for 16 h. Filter the reaction mixture by suction, concentrate the filtrate to dryness, and purify the residue by silica gel column chromatography (EA:PE, EA from 0 to 35%) to obtain colorless oil 8-A (250 mg, 706.14 umol). (ESI) m / z = 346.9 (M+1) + . 1 H NMR (400 MHz, CDCl3) Shift 7.48 (s, 1H), 6.83 (s, 1H), 5.61 - 5.77 (m, 1H), 5.32 (s, 2H), 3.86 (s, 3H), 3.81 (q, J = 7.09 Hz, 2H), 2.53 - 2.81 (m, 3H), 2.02 - 2.28 (m, 1H), 1.26 (t, J = 7.03 Hz, 3H)

[0358] Step 4 (Representative operation of Suzuki coupling reaction): Add K3PO4 (129 mg, 608.37 umol) and XPhos Pd G3 (17.17 mg, 20.28 umol) to a mixture of compound 8-A (70 mg, 202.79 umol) and phenylboronic acid (74.18 mg, 608.37 umol) in THF / water (3 mL, 4 / 1), degas and refill with nitrogen twice. Heat it to 60 °C and react for 1 h. Concentrate the reaction mixture to dryness, dilute the reaction with ethyl acetate (3 mL). After conventional post-treatment operations, a crude product is obtained, and the crude product is purified by silica gel thin layer chromatography separation (PE:EA = 1:1) to obtain yellow oil compound 8-B (60 mg, yield 82.09%). LCMS: (ESI) m / z = 343.2 (M+1) + ; 1 HNMR (400 MHz, CHLOROFORM-d) Shift 7.44 - 7.52 (m, 2H), 7.35 - 7.43 (m, 2H), 7.27 - 7.33 (m, 2H), 6.89 (s, 1H), 5.67 - 5.82 (m, 1H), 5.18 (s, 2H), 3.89 (s, 3H), 3.66 (dq, J = 1.16, 7.07 Hz, 2H), 2.56 - 2.74 (m, 3H), 2.13 - 2.28 (m, 1H), 1.20 (t, J = 7.09 Hz, 3H).

[0359] Step 5: A solution of compound 8-B (80 mg, 0.23 mmol) in DCM (3.5 mL) and TFA (0.35 mL) was stirred at 20 °C for 2 h. The reaction was quenched with saturated NaHCO3 solution (2 mL), and the mixture was extracted with DCM (3 mL × 3). After conventional post-treatment operation 2, a residue was obtained. The residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to give white solid compound 8 (35 mg, yield 50%). LCMS: (ESI) m / z = 284.9 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) Shift 9.81 (s, 1H), 7.51 (d, J = 7.03 Hz, 2H), 7.38 (t, J = 7.65 Hz, 2H), 7.22 - 7.30 (m, 1H), 7.19 (s, 1H), 6.63 (s, 1H), 5.67 (t, J = 7.53 Hz, 1H), 3.80 (s, 3H), 2.54 - 2.73 (m, 2H), 2.43 - 2.50 (m, 1H), 2.12 - 2.25 (m, 1H).

[0360] Referring to the synthesis method of compound 8, the starting materials in the following table were reacted with compound 8-A to obtain the corresponding final product compounds.

[0361]

[0362]

[0363] Synthesis of Compound 11 in Example 9

[0364]

[0365] Step 1: To a mixture of compound 8-A (100 mg, 0.29 mmol) in dioxane / water (4 mL, 1 / 1), add potassium ferrocyanide (53.35 mg, 144.85 μmol), potassium acetate (3.55 mg, 36.21 μmol), t-Bu Xphos (2.46 mg, 5.79 μmol, 0.02 eq), and t-Bu Xphos Pd G3 (2.30 mg, 2.90 μmol). Degas and fill with nitrogen. Heat the mixture to 80 °C and react for 2 hours. LCMS shows a small amount of starting material remaining, but the target product has been formed. Cool the reaction mixture to room temperature and extract with EA (5 mL × 3). After conventional post-treatment operation two, the crude product is obtained. The crude product is purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 30%) to give compound 11-A as a colorless oil (60 mg, yield 35.5%). LCMS: (ESI) m / z = 292.2 (M + 1) + .

[0366] Step 2: Stir a solution of compound 11-A (50 mg, 0.17 mmol) in DCM (1 mL) and TFA (0.5 mL) at 25 °C for 1 hour. Quench the reaction with saturated NaHCO3 solution (1 mL). Extract the mixture with EA (3 mL × 3). Adjust the pH of the aqueous phase to 3 - 4 with 1 M HCl and extract again with EA (5 mL × 3). After conventional post-treatment operation two, a residue is obtained. The residue is washed with DCM (1 mL) to give compound 11 as a white solid (35 mg, yield 50%). LCMS: (ESI) m / z = 234.1 (M + 1) + . 1 HNMR (400 MHz, DMSO-d6) Shift 7.44 (s, 1H), 6.54 (s, 1H), 4.74 (dd, J = 4.39, 7.40 Hz, 1H), 3.80 (s, 3H), 2.16 - 2.25 (m, 2H), 1.77 - 1.90 (m, 1H), 1.62 - 1.75 (m, 1H).

[0367] Synthesis of Compound 12 in Example 10

[0368]

[0369] Step 1: Add NaHCO3 (3.91 g, 46.50 mmol) and benzyl bromide (3.98 g, 23.25 mmol) to a mixture of compound 12-A (5.76 g, 21.1 mmol) in acetonitrile (60 mL). Heat the mixture to 82 °C and react for 16 hours. After the reaction solution cools to room temperature, add water (80 mL) and extract with EA (100 mL). After conventional post-treatment operation 2, a crude product is obtained. The crude product is purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 29%) to obtain yellow solid compound 12-B (4.6 g, yield 60.73%).

[0370] Step 2: Add 12-C (811 mg, 2.72 mmol) and cesium fluoride (826 mg, 5.44 mmol) to a mixture of compound 12-B (650 mg, 1.81 mmol) in acetonitrile (26 mL). React at 20 °C for 16 hours. Add saturated brine (20 mL) and extract with EA (20 mL). After conventional post-treatment operation 2, a crude product is obtained. The crude product is purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 20%) to obtain yellow oily substance 12-D (238 mg, yield 30.22%). 1 HNMR (400 MHz, DMSO-d6) δ ppm 1.10 - 1.14 (m, 3H) 2.44 - 2.47 (m, 2H) 2.95 - 3.02 (m, 2H) 3.77 - 3.82 (m, 3H) 3.97 - 4.01 (m, 2H) 5.02 - 5.09 (m, 2H) 6.07 - 6.12 (m, 1H) 6.54 - 6.59 (m, 1H) 7.11 - 7.38 (m, 10H)

[0371] Step 3: Refer to the method of representative catalytic hydrogenation operation and react compound 12-D (235 mg, 541 μmol) to obtain yellow colloidal product 12-E (120 mg, 349 μmol). Purification method: silica gel column chromatography purification (EA:PE, EA from 0 to 15%) 11H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 8.53 Hz, 1H), 7.76 (s, 1H), 7.29 - 7.57 (m, 9H), 6.96 (d, J = 8.53 Hz, 1H), 6.23 (br t, J = 5.52 Hz, 1H), 4.75 (d, J = 5.52 Hz, 2H), 4.17 - 4.30 (m, 2H), 3.89 (s, 3H), 3.68 (s, 3H), 2.76 (t, J = 7.53 Hz, 2H), 2.41 (t, J = 7.53 Hz, 2H), 2.01 (t, J = 7.40 Hz, 2H), 1.77 - 1.88 (m, 4H), 1.63 - 1.77 (m, 3H), 1.32 - 1.44 (m, 1H), 1.15 - 1.29 (m, 3H), 0.94 - 1.09 (m, 2H).

[0372] Step 4 (Representative operation of ester hydrolysis): Lithium hydroxide monohydrate (36.7 mg, 0.87 mmol, about 2.5 equivalents) was added to a mixture of compound 12-E (120 mg, 0.35 mmol) in THF (1 mL) and MeOH (1 mL). The reaction was carried out at 65 °C for 16 hours (LCMS showed complete reaction). The reaction solution was cooled to room temperature, and the pH was adjusted to 1 - 2 with 2M HCl, and then extracted with EA (4 mL * 3). After conventional post-treatment operations, the crude product was obtained, and the crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 24% - 73%) to obtain yellow oil 12-F (65 mg, yield 58.82%). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 - 2.48 (m, 2H) 2.95 - 3.03 (m, 2H) 3.53 - 3.53 (m, 1H) 3.71 - 3.78 (m, 3H) 5.78 - 5.87 (m, 1H) 6.20 - 6.26 (m, 1H) 6.97 - 7.03 (m, 2H) 7.12 - 7.19 (m, 1H) 7.34 - 7.44 (m, 2H) 9.95 - 10.01 (m, 1H)

[0373] Step 5: Referring to the representative operation for constructing a five-membered lactone ring, compound 12-F (65 mg, 205 μmol) was reacted to obtain white solid compound 12 (10 mg, yield 16.2%). 11H NMR (400 MHz, DMSO-d6) δ ppm 1.54 - 1.60 (m, 2H) 2.06 - 2.11 (m, 2H) 2.41 - 2.46 (m, 2H) 3.65 - 3.72 (m, 6H) 5.98 - 6.07 (m, 2H) 9.21 - 9.30 (m, 1H) 11.78 - 11.91 (m, 1H). LCMS: (ESI) m / z = 301.0 (M+1) + .

[0374] Synthesis of Compound 13 in Example 11

[0375]

[0376] Step 1: Under the conditions of 0 °C and nitrogen protection, a solution of potassium tert-butoxide (1 M, 25.93 mL) in THF was added dropwise to a mixture of methyltriphenylphosphonium bromide (Ph3PMeBr, 10.65 g, 29.82 mmol) in THF (80 mL), and the mixture was stirred at 0 °C for 1 hour. At 0 °C, a solution of Compound 13-A (4 g, 12.97 mmol) in THF (60 mL) was added to the above reaction mixture. The temperature was raised to room temperature (20 °C) and the reaction was carried out for 16 hours. At 0 - 10 °C, the reaction was quenched with saturated NH4Cl solution (5 mL), water (8 mL) was added, and the mixture was extracted with MTBE (4 mL * 3). After conventional post-treatment operation two, the crude product was obtained. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 4%) to obtain a yellow solid compound 13-B (2.03 g, yield 51%). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 - 1.12 (m, 18H) 1.21 - 1.30 (m, 3H) 3.72 - 3.77 (m, 3H) 5.07 - 5.14 (m, 1H) 5.59 - 5.66 (m, 1H) 6.39 - 6.48 (m, 2H) 6.77 - 6.90 (m, 1H) 7.34 - 7.39 (m, 1H).

[0377] Step 2: Add 13-C (584 mg, 2.72 mmol), H2O (97.9 mg, 5.44 mmol), and diiron nonacarbonyl (cas: 15321-51-4, 49.4 mg, 135.94 μmol) to a mixture of 13-B (1 g, 3.26 mmol, 1.2 eq) in DMF (10 mL). React at 80 °C for 16 h. Cool to room temperature, add water (4 mL), and extract with EA (12 mL). After conventional post-treatment operation 2, a crude product is obtained. The crude product is purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 7% to 11.5%) to obtain a white solid compound 13-D (157 mg, yield 13.11%). Its structure may be cis or trans and was not further identified. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11 - 1.14 (m, 18H) 1.25 - 1.32 (m, 3H) 2.66 - 2.85 (m, 2H) 3.79 - 3.83 (m, 3H) 3.91 - 3.98 (m, 1H) 5.78 - 5.87 (m, 1H) 6.44 - 6.54 (m, 2H) 7.12 - 7.22 (m, 1H) 7.30 - 7.41 (m, 5H).

[0378] Step 3: Add TEA(HF)3 (14.6 mg, 90.78 μmol) to a mixture of 13-D (50 mg, 113.47 μmol) in THF (1 mL). React at 20 °C for 2 h. After completion of the reaction, add saturated aqueous NaHCO3 solution to adjust the pH to 7 - 8, and extract with EA (2 mL × 3). After conventional post-treatment operation 2, a crude product is obtained. The crude product is purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 62%) to obtain a yellow solid compound 13 (9 mg, yield 27.9%). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.40 (m, 0.6H), 2.66 - 2.75 (m, 0.4H), 2.76 - 2.87 (m, 0.4H), 3.09 (m, 0.6H), 3.95 (m, 0.4H), 4.04 (m, 0.6H), 5.00 (br s, 1H) 5.73 (dd, J = 10.5, 5.8 Hz, 0.6H), 5.85 (dd, J = 7.8, 4.8 Hz, 0.4H), 6.38 - 6.57 (m, 2H), 7.09 - 7.25 (m, 1H), 7.31 - 7.60 (m, 5H)

[0379] Synthesis of Compound 16 in Example 12

[0380]

[0381] Step 1: Add allyl bromide (235 mg, 1.95 mmol) and K2CO3 (358 mg, 2.60 mmol) to a mixture of 16-A (300 mg, 1.3 mmol) in DMF (6 mL). React at 25 °C for 2 hours. Add water (6 mL), and extract with EA (8 mL x 3). After conventional post-treatment operations, the crude product is obtained. The crude product is purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 30%) to obtain a yellow oil 16-B (220 mg, yield 62.5%). LCMS: (ESI) m / z = 273.0 (M+1) + .

[0382] Step 2: Add 16-C (655 mg, 3.76 mmol) and ZnI2 (360 mg, 1.13 mmol) to a solution of 16-B (170 mg, 0.63 mmol) in DCM (4 mL). React at 25 °C for 16 hours. Add water (5 mL), and extract with DCM (3 mL x 3). After conventional post-treatment operations, a brown oil 16-D (280 mg) is obtained and directly used in the next reaction.

[0383] Step 3: Add water (33.9 mg, 1.89 mmol) to a solution of compound 16-D (280 mg) in DCM (4 mL) and TFA (0.4 mL), and react at 25 °C for 16 hours. After the reaction is completed, under the condition of 5 °C - 10 °C, add saturated aqueous NaHCO3 solution to adjust the pH to 7 - 8, and extract with DCM (2 mL x 3). After conventional post-treatment operations, the crude product is obtained. The crude product is purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 50%) to obtain a yellow oil 16-E (17 mg, purity 74%). LCMS: (ESI) m / z = 327.0 [M+H] + .

[0384] Step 4: Under nitrogen protection, add Pd(PPh3)4 (6 mg, 5.2 μmol) and PPh3 (14.99 mg, 57.16 μmol) to a solution of compound 16-E (17 mg) in THF (0.5 mL), and react at 25 °C for 16 hours. After the reaction is completed, concentrate under reduced pressure, and the obtained residue is purified by prep-HPLC (FA method; B%: 23% - 53%, 8 min) to obtain a white solid compound 16 (1 mg, 3.36 umol, three-step yield about 5.3%). (ESI) m / z = 286.9 [M+H] + ). 11H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.70 (d, J = 2.32 Hz, 1H) 6.43 (d, J = 2.32 Hz, 1H) 6.12 (dd, J = 8.86, 6.91 Hz, 1H) 5.90 (brs, 1H) 3.75 (s, 3H) 2.65 - 2.82 (m, 2H) 2.51 - 2.64 (m, 1H) 2.35 - 2.46 (m, 1H).

[0385] Referring to the methods of Step 2 to Step 4 in Example 12 (representative operation - A for constructing the five - membered lactone ring), the corresponding final product compounds were obtained by three - step reactions using the starting materials in the following table.

[0386]

[0387] The synthetic method of the starting material 87 - A involved in the above table is as follows:

[0388]

[0389] To a solution of compound 73 - A (300 mg, 1.03 mmol) in DMF (5 mL), compound 87 - B (395 mg, 2.06 mmol), potassium fluoride (59.8 mg, 1.03 mmol), and CuI (196 mg, 1.03 mmol) were added. It was heated to 80 °C and reacted for 16 hours under light - protected conditions. After cooling to room temperature, it was filtered and washed with EA. The filtrate was subjected to the conventional post - treatment operation 2 to obtain the crude product, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain the gray solid compound 87 - A (280 mg, yield 97%). LCMS: (ESI) m / z = 280.9 (M + 1) +

[0390] Synthesis of Compound 65 in Example 12 - a

[0391]

[0392] Step 1: A mixture of 47-B (3.6 g, 18.5 mmol), N-(2-methoxyethyl)methylamine (3.30 g, 37.1 mmol) and K2CO3 (5.12 g, 37.1 mmol, 2 eq) in dioxane (80 mL) was reacted at 120 °C for 40 h. LC-MS showed that ~32% of the starting material remained and ~65% of the target product was formed. The reaction was diluted with EA (100 mL), filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 15%) to give 65-A as a yellow oil (3.7 g, yield 75.8%). LCMS: (ESI) m / z = 264.3 (M+1) + .

[0393] Steps 2 and 3: Referring to the methods of Steps 2 and 3 in Example 12, a two-step reaction was carried out with 65-A to give compound 65-B as an orange oil, and the two-step yield was about 20%. LC-MS: (ESI) m / z. [M+H] + 320.3

[0394] Step 4: Referring to the method of Step 3 in Example 2, a reaction was carried out with 65-A to give 65 as a yellow oil, with a yield of 63%. LC-MS: (ESI) m / z. [M+H] + 280.3; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.39 (s, 1H), 7.05 (s, 1H), 6.66 (s, 1H), 5.87 (dd, J = 6.8, 9.0 Hz, 1H), 3.37 (t, J = 5.9 Hz, 2H), 3.22 (s, 3H), 2.84 - 2.98 (m, 2H), 2.63 - 2.75 (m, 1H), 2.53 - 2.62 (m, 4H), 2.44 (m, 1H), 2.08 - 2.16 (m, 1H), 2.07 (s, 3H).

[0395] Synthesis of Compound 66 in Example 12-b

[0396]

[0397] Step 1: At -78 °C, a solution of compound 66-A (5 g, 29.4 mmol) in THF (50 mL) was added dropwise with cyclopropylmagnesium bromide solution (0.5 M, 205 mL), and it was allowed to rise to room temperature of 25 °C naturally and reacted for 16 h. After the reaction was completed, saturated NH4Cl aqueous solution (200 mL) was added to quench the reaction, and it was extracted with EtOAc (200 mL * 3). After conventional post-treatment operation 2, the crude product yellow solid 66-B (7.6 g) was obtained. LC-MS: (ESI) m / z. [M-OH] +205.1.

[0398] Step 2: At -30 °C, Et3SiH (5.23 g, 45 mmol) and TFA (10.2 g, 90.0 mmol) were added dropwise to a solution of 66-B (5 g) in DCM (100 mL). The temperature was maintained at -30 °C to -20 °C for 2 h. After completion of the reaction, water (100 mL) was added, and the pH was adjusted to 8 - 9 with saturated sodium carbonate solution. The mixture was extracted with DCM (50 mL × 3). After conventional post-treatment operation 2, the crude product was obtained and purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to give colorless oil 66-C (5.14 g, yield about 83% in two steps). 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.23 (dd, J = 7.3, 8.4 Hz, 1H), 6.64 (dt, J = 2.6, 8.4 Hz, 1H), 6.49 (dd, J = 2.5, 10.6 Hz, 1H), 1.95 (t, J = 8.6 Hz, 1H), 1.03 - 1.12 (m, 2H), 0.95 - 1.03 (m, 9H), 0.73 - 0.82 (m, 6H), 0.48 - 0.58 (m, 2H), 0.22 - 0.34 (m, 4H), 0.04 - 0.12 (m, 2H).

[0399] Step 3: Triethylamine trihydrofluoride (5.17 g, 32.1 mmol) was added to a solution of compound 66-C (5.14 g, 16 mmol) in ACN (60 mL), and the reaction was carried out at 25 °C for 16 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was dissolved in EtOAc (100 mL). After conventional post-treatment operation 2, the crude product was obtained and purified by silica gel column chromatography (EA:PE, EA from 0 to 3.5%) to give colorless oil 66-D (3.2 g, yield 88%). 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.19 (dd, J = 6.7, 8.50 Hz, 1H), 6.63 (dt, J = 2.5, 8.4 Hz, 1H), 6.53 (dd, J = 2.5, 10.0 Hz, 1H), 5.22 (s, 1H), 1.97 (t, J = 8.0 Hz, 1H), 1.12 (tq, J = 5.1, 8.0 Hz, 2H), 0.53 - 0.65 (m, 2H), 0.36 - 0.46 (m, 2H), 0.31 (qd, J = 4.8, 9.4 Hz, 2H), 0.06 - 0.19 (m, 2H).

[0400] Step 4: NBS (949 mg, 5.33 mmol) was added to a solution of compound 66-D (1 g, 4.85 mmol) in DCM (30 mL), and the reaction was carried out at 25 °C for 16 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain colorless oil 66-E (610 mg, yield 44%). 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.38 (d, J = 7.8 Hz, 1H), 6.61 (d, J = 9.4 Hz, 1H), 5.24 (s, 1H), 1.92 (t, J = 8.1 Hz, 1H), 1.09 (tq, J = 5.1, 8.1 Hz, 2H), 0.54 - 0.68 (m, 2H), 0.38 - 0.50 (m, 2H), 0.32 (qd, J = 4.8, 9.57 Hz, 2H), 0.08 - 0.19 (m, 2H).

[0401] Steps 5 and 6: Referring to the methods of steps 2 and 3 in Example 21, two-step reaction was carried out using 66-E as the starting material to obtain yellow oil 66-G (two-step yield about 46.74%). 1 H NMR (400 MHz, CDCl3) δ (ppm) 10.25 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 12.5 Hz, 1H), 6.04 (tdd, J = 5.1, 10.5, 17.3 Hz, 1H), 5.43 (qd, J = 1.5, 17.3 Hz, 1H), 5.35 (qd, J = 1.3, 10.6 Hz, 1H), 4.61 (td, J = 1.5, 5.1 Hz, 2H), 1.90 (t, J = 8.9 Hz, 1H), 1.06 - 1.23 (m, 2H), 0.53 - 0.64 (m, 2H), 0.26 - 0.37 (m, 4H), 0.01 - 0.11 (m, 2H).

[0402] Step 7: Referring to the method of step 1 in Example 12-a, reaction was carried out using 66-G (210 mg) as the starting material to obtain yellow oil 66-H (200 mg, yield 76.07%). LC-MS: (ESI) m / z. [M+H] + 344.2

[0403] Steps 8 and 9: Referring to the methods of steps 2 and 3 in Example 2, two-step reaction was carried out starting from 66-H to obtain off-white solid compound 66, two-step yield about 51%. 11H NMR (400 MHz, DMSO-d6) δ (ppm) 9.15 - 9.43 (m, 1H), 6.94 - 7.20 (m, 1H), 6.60 - 6.80 (m, 1H), 5.63 - 6.02 (m, 1H), 3.42 - 3.45 (m, 2H), 3.19 - 3.29 (m, 3H), 2.89 - 3.04 (m, 2H), 2.57 - 2.69 (m, 3H), 2.28 - 2.36 (m, 1H), 2.11 - 2.27 (m, 1H), 1.67 - 1.79 (m, 1H), 1.28 (dt, J = 4.7, 8.35 Hz, 1H), 1.03 - 1.15 (m, 2H), 0.74 - 0.99 (m, 1H), 0.41 - 0.54 (m, 2H), 0.17 - 0.30 (m, 4H), -0.09 - 0.03 (m, 2H). LC-MS: (ESI) m / z. [M+H] + 372.4

[0404] Synthesis of Compound 17 in Example 13

[0405]

[0406] Step 1: Refer to the method in Step 1 of Example 2. Step 2: Refer to the method in Step 2 of Example 2. Step 3: Refer to the method in Step 4 of Example 12. Perform a three-step reaction with the starting materials in the following table to obtain Compound 17.

[0407]

[0408]

[0409] Refer to the methods in Step 2 and Step 3 of Example 13. Perform a two-step reaction with the starting materials in the following table to obtain the final product compound.

[0410]

[0411] Synthesis of Compound 18 in Example 14

[0412]

[0413] Step 1: Refer to the method in Step 4 of Example 8-b. React 15-A (2.0 g, 9.30 mmol) with 18-A (2.90 g, 13.95 mmol) to obtain a off-white solid compound 18-B (1.96 g, yield 84.17%). LCMS: (ESI) m / z = 217.0 (M + 1) + .

[0414] Steps 2 to 4: Referring to the method in Example 13, perform a three-step reaction with the starting materials in the following table to obtain the final product compound.

[0415]

[0416]

[0417] The synthesis method of the starting material 82-A involved in the above table is as follows:

[0418]

[0419] Referring to the method in Step 4 of Example 8-b, react compound 67-A (750 mg, 2.99 mmol) with 18-A (932 mg, 1.5 eq) to obtain the yellow solid compound 82-A (750 mg, yield 99%). LCMS: (ESI) m / z = 253.0 (M+1) +

[0420] Referring to the method of the starting material 82-A, replace 18-A with the starting materials in the following table and react with compound 67-A to obtain the intermediate compound.

[0421]

[0422] Synthesis of Compound 19 in Example 15

[0423]

[0424] Step 1: Referring to the method in Step 1 of Example 2, prepare the yellow oil 19-B (1.6 g, 24.83% yield) from 19-A (5.1 g, 33.52 mmol). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H)

[0425] 4.64 (d, J = 5.00 Hz, 2H) 5.30 (dd, J = 10.63, 1.38 Hz, 1H) 5.42 (dd, J = 17.26, 1.63 Hz, 1H) 6.00 - 6.11 (m, 1H) 6.50 (s, 1H) 7.45 (s, 1H) 9.96 (s, 1H) 10.89 (s, 1H)

[0426] Step 2: To a solution of compound 19-B (400 mg, 2.08 mmol) in acetonitrile (8 mL) was added K2CO3 (575 mg, 4.16 mmol) and iodoethane (486 mg, 3.12 mmol), and the mixture was stirred at 25 °C for 16 h. The solvent was removed by concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to give white solid 19-C (210 mg, 45.81%). (ESI) m / z = 245.2 (M+Na) + .

[0427] Steps 3 and 4: Referring to the methods of steps 2 and 3 in Example 2, two-step reaction was carried out with 19-C (573 mg, 2.41 mmol) to obtain yellow solid compound 19 (45 mg, overall yield of two steps was about 15.8%). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.78 - 0.86 (m, 1H) 0.95 - 1.07 (m, 1H) 1.28 - 1.36 (m, 1H) 1.38 - 1.44 (m, 3H) 2.10 - 2.20 (m, 4H) 2.21 - 2.28 (m, 1H) 2.64 - 2.72 (m, 1H) 3.90 - 4.13 (m, 2H) 4.75 - 5.10 (m, 1H) 5.35 - 5.54 (m, 1H) 5.83 (d, J = 4.63 Hz, 1H) 6.33 - 6.46 (m, 1H) 6.87 - 7.02 (m, 1H). LCMS: (ESI) m / z = 249.1 (M+1) +

[0428] Synthesis of Compound 21 in Example 16

[0429]

[0430] Referring to the method of Example 2, starting from 19-B and benzyl bromide, three-step reaction was carried out to obtain white solid compound 21 (45 mg, overall yield of three steps was about 1.4%). LCMS: (ESI) m / z = 311.1 [M+H] + , 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32 - 7.48 (m, 5H) 6.94 - 7.09 (m, 1H) 6.46 - 6.56 (m, 1H) 5.52 - 5.91 (m, 1H) 5.02 - 5.16 (m, 2H) 4.71 - 4.87 (m, 1H) 2.23 - 2.70 (m, 1H) 2.20 (s, 3H) 2.00 - 2.17 (m, 1H) 1.30 (m, 1H) 0.97 - 1.07 (m, 1H).

[0431] Referring to the method in Example 16, the starting materials in the following table were used to replace benzyl bromide for a three-step reaction to obtain the final product compound.

[0432]

[0433]

[0434] Synthesis of Compound 20 in Example 17

[0435]

[0436] Step 1: Under ice bath conditions, compound 19-B (1 g, 5.20 mmol) was added to a solution of potassium tert-butoxide (1 M THF solution, 7.80 mL) in THF (20 mL), and the mixture was stirred at 0 °C for 6 minutes. Then, 20-A (CAS: 66003-76-7, 2.91 g, 6.76 mmol, 1.3 eq) was added. The reaction mixture was allowed to warm to room temperature (25 °C) and stirred for 2 hours. The reaction solution was added to ice water (20 mL), and the mixture was extracted with EtOAc (15 mL x 3). After conventional post-treatment operations, the crude product was obtained. The crude product was purified by silica gel thin layer chromatography (EA:PE, EA from 0 to 3%) to obtain a yellow oil, 20-B (290 mg, yield 21%). 1 H NMR (CDCl3, 400 MHz) δ ppm 10.31 (s, 1H) 7.75 (s, 1H) 7.35 - 7.48 (m, 2H) 7.13 - 7.21 (m, 1H) 7.00 - 7.10 (m, 2H) 6.34 (s, 1H)

[0437] 5.91 - 6.03 (m, 1H) 5.23 - 5.39 (m, 2H) 4.41 - 4.53 (m, 2H) 2.25 (s, 3H).

[0438] Steps 2 and 3: Referring to the methods of Steps 3 and 4 in Example 2, two-step reaction was carried out using 20-B to obtain white solid compound 20 (6 mg, two-step yield about 3.5%). LCMS: (ESI) m / z = 297.1 [M + H] + , 1 H NMR (CDCl3, 400 MHz) δ ppm 8.25 - 8.31 (m, 1H) 8.09 (d, J = 8.56 Hz, 1H) 7.58 - 7.67 (m, 1H) 7.49 - 7.57 (m, 1H) 6.88 - 6.93 (m, 1H) 6.34 (s, 1H) 2.51 - 2.61 (m, 1H) 2.38 - 2.47 (m, 1H) 1.63 (br s, 1H) 1.32 - 1.37 (m, 1H).

[0439] Synthesis of Compound 23 in Example 18

[0440]

[0441] Step 1: To a solution of 19-B (500 mg, 2.60 mmol) in MeCN (10 mL) was added Compound 23-A (664 mg, 2.86 mmol) and cesium carbonate (1.70 g, 5.20 mmol). The reaction was carried out at 80 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). After conventional post-treatment operations, the crude product was obtained and purified by silica gel thin-layer chromatography (EA:PE, EA from 0 to 30%) to give yellow solid 23-B (300 mg, yield 42%). 1 1H NMR (CDCl3, 400 MHz) δ ppm 10.32 (s, 1H) 7.70 (s, 1H) 6.37 (s, 1H) 6.00 - 6.18 (m, 1H) 5.48 (dd, J = 17.17, 1.32 Hz, 1H) 5.38 (dd, J = 10.56, 1.32 Hz, 1H) 4.62 - 4.68 (m, 2H) 4.47 (q, J = 8.00 Hz, 2H) 2.23 (s, 3H)

[0442] Steps 2 and 3: Referring to the methods of Steps 3 and 4 in Example 2, two-step reaction was carried out with 23-B to give white solid Compound 23 (10 mg, two-step yield about 2.5%). LCMS: (ESI) m / z = 303.1 [M+H] + , 1 1H NMR (DMSO-d6, 400 MHz) δ ppm 9.29 - 10.19 (m, 1H) 6.83 - 7.09 (m, 1H) 6.48 - 6.61 (m, 1H) 5.30 - 5.80 (m, 1H) 4.61 - 4.82 (m, 2H) 2.15 - 2.28 (m, 2H) 2.02 - 2.11 (m, 3H) 1.03 - 1.36 (m, 1H) 0.66 - 1.01 (m, 1H).

[0443] Synthesis of Compound 33 in Example 19

[0444]

[0445] Step 1: To a solution of Compound 19-B (500 mg, 2.60 mmol) and Compound 33-A (562 mg, 3.12 mmol) in DMF (10 mL) was added K2CO3 (1.08 g, 7.8 mmol), and the reaction was carried out at 90 °C for 15 hours. After cooling to room temperature, the reaction mixture was diluted with saturated brine (50 mL) and extracted with EtOAc (50 mL x 2). After conventional work-up, the crude product was obtained and purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to give yellow solid Compound 33-B (580 mg, yield 80.7%).

[0446] Steps 2 and 3: Referring to the methods of Steps 2 and 3 in Example 2, two-step reaction was carried out to obtain white solid 33 (total yield of two steps was about 46%). LCMS: (ESI) m / z = 305.1 (M+H) + ; 1 H NMR (400 MHz, DMSO-d6) Shift 9.48 (s, 1H), 6.94 (s, 1H), 6.51 - 6.57 (m, 1H), 5.36 (s, 1H), 4.37 - 4.51 (m, 1H), 3.86 (td, J = 4.22, 11.32 Hz, 2H), 3.39 - 3.55 (m, 2H), 2.13 - 2.33 (m, 2H), 2.04 (s, 3H), 1.92 - 2.00 (m, 2H), 1.50 - 1.71 (m, 2H), 1.30 (dt, J = 4.38, 8.13 Hz, 1H), 0.90 (br s, 1H)

[0447] Referring to the method in Example 19, the starting materials in the following table were used to replace 33-A to carry out a three-step reaction to obtain the final product compound.

[0448]

[0449]

[0450] Synthesis of Compound 38 in Example 20

[0451]

[0452] At 20 °C (room temperature), tetrabutylammonium fluoride (122.37 mg, 468.04 μmol) was added to a solution of compound 37 (120 mg, 312.03 μmol) in THF (2 mL). The reaction was stirred at 20 °C for 3 hours. After completion of the reaction, the reaction was quenched with water (3 mL), and extracted with EA (3 mL × 3). After conventional post-treatment operation 2, it was purified by prep HPLC (FA method, B: 20%-50% for 8 min) to obtain white solid compound 2 (15 mg, yield 19.6%). 1 HNMR(400MHz,DMSO-d6)δ9.65-10.02(m,1H)6.96-7.10(m,1H)6.89-6.94(m,1H)5.86(d,J=4.84Hz,0.28H)5.53(s,0.81H)4.38-4.48(m,1H)2.28(dd,J=8.36,3.74Hz,2H)2.10-2.18(m,3H)1.34(td,J=8.36,4.62Hz,1H)1.03-1.17(m,1H).LC-MS:(ESI)m / z=229.0[M+H] + .

[0453] Synthesis of Compound 59 in Example 21

[0454]

[0455] Step 1: Compound 59-A (6 g, 29 mmol) was reacted in a solution of tert-butanol (60 mL) and concentrated sulfuric acid (7.5 mL) at 40 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water, and extracted with EtOAc (50 mL x 3). After conventional post-treatment operation 2, the crude product was obtained and purified by silica gel column chromatography (EA:PE, EA from 0 to 10%) to obtain white solid compound 59-B (2.2 g, yield 28.73%). 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.70(s,1H),7.16(s,1H),6.48-6.56(m,1H),3.74(s,3H),1.29(s,9H).

[0456] Step 2: Referring to the method in Step 1 of Example 12, compound 59-B (2.2 g) was reacted to obtain white solid 59-C (2.2 g, yield 86%). LCMS: (ESI) m / z = 273.0 (M + 1) + . 11H NMR (400 MHz, DMSO-d6) δ (ppm) 7.25 (s, 1H), 6.74 (s, 1H), 6.04 - 6.18 (m, 1H), 5.46 (dd, J = 1.8, 17.39 Hz, 1H), 5.30 (dd, J = 1.7, 10.7 Hz, 1H), 4.67 (d, J = 5.1 Hz, 2H), 3.83 (s, 3H), 1.28 - 1.34 (m, 9H).

[0457] Step 3: At -60 °C, add a THF solution of n-butyllithium (2.5 M, 3.2 mL) to a THF (20 mL) solution of compound 59-C (2.00 g, 6.7 mmol). After stirring for 0.5 h, add DMF (977 mg, 13 mmol). Raise the temperature to 25 °C and continue stirring the reaction for 3 h. Quench the reaction by adding an NH4Cl solution (20 mL). Extract the mixture with EA (30 mL × 3). After conventional post-treatment operation 2, purify by silica gel column chromatography (THF:PE, THF from 0 to 30%) to obtain white solid 59-D (0.61 g, yield 37%). LCMS: (ESI) m / z = 249.2 (M +

[0458] H) + .

[0459] Steps 4 and 5: Refer to the methods of steps 2 and 3 in Example 2. Start with 59-D (585 mg, 2.5 mmol) and carry out a two-step reaction to obtain white solid compound 59, with a two-step yield of approximately 4.5%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.48 - 9.66 (m, 1H), 6.90 - 7.03 (m, 1H), 6.43 - 6.56 (m, 1H), 5.33 - 5.80 (m, 1H), 3.69 - 3.78 (m, 3H), 2.13 - 2.26 (m, 2H), 1.07 - 1.37 (m, 10H), 0.66 - 0.98 (m, 1H). LC-MS: (ESI) m / z. [M + H] + 277.3

[0460] Synthesis of Compound 67 in Example 22

[0461]

[0462] Step 1: Add chloromethyl ethyl ether (1.58 g, 16.73 mmol) and K2CO3 (3.47 g, 25.09 mmol) to a solution of 16-A (2.1 g, 8.36 mmol) in DMF (40 mL). React at 25 °C for 5 h. Add water (50 mL), and extract with EA (50 mL x 3). After conventional post-treatment operation two, a crude product is obtained. The crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 3%) to obtain a white solid 67-B (2.3 g, yield 89%). LCMS: (ESI) m / z = 308.9 (M+1) + .

[0463] Steps 2 and 3: Refer to the methods in Steps 2 and 3 of Example 12 (representative operation - B for constructing a five-membered lactone ring), and perform two-step reaction with 67-B to obtain a white solid compound 67, with a two-step yield of about 17.2%. LCMS: (ESI) m / z = 306.9 [M+H] + , 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 7.19 Hz, 1H), 7.98 (d, J = 7.43 Hz, 1H), 7.51 - 7.60 (m, 2H), 7.32 (s, 1H), 6.50 (t, J = 8.50 Hz, 1H), 5.43 - 5.50 (m, 2H), 3.82 (q, J = 7.00 Hz, 2H), 2.83 - 2.94 (m, 2H), 2.61 - 2.71 (m, 2H), 1.28 (t, J = 7.07 Hz, 3H).

[0464] Refer to the method in Example 22 (representative operation - C for constructing a five-membered lactone ring), and perform a three-step reaction with the starting materials in the following table to obtain the final product compound.

[0465]

[0466] The synthesis method of the starting material 78-A involved in the above table is as follows:

[0467]

[0468] Refer to the synthesis method of intermediate 40-A, and react with compound 78-B (440 mg, 2.46 mmol) to obtain a yellow solid compound 78-A (400 mg, yield 78%). LCMS: (ESI) m / z = 207.0 (M+1) +

[0469] Refer to the methods in Steps 2 and 3 of Example 22 (representative operation - B for constructing a five-membered lactone ring), and perform a reaction with the starting materials in the following table to obtain the final product compound.

[0470]

[0471] The synthetic method of the starting material 78-A involved in the above table is as follows:

[0472]

[0473] Referring to the method of Example 37, using 78-A (60 mg) as the raw material, the yellow solid compound 144-A (50 mg, yield 69%) was obtained. LCMS: (ESI) m / z = 248.9 [M+H] + 。

[0474] Synthesis of Compounds 71 and 72 in Example 23

[0475]

[0476] Acetic anhydride (22.4 mg, 219.77 μmol) was added to a pyridine (1 mL) solution of compound 67 (45 mg, 146.51 μmol). The reaction was carried out at 25 °C for 16 hours. Water (3 mL) was added, and the mixture was extracted with EA (2 mL x 3). After conventional post-treatment operations, the crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 50%) and then by SFC chiral resolution to obtain the white solid compounds 71 (5 mg) and 72 (5 mg).

[0477] The conditions for chiral separation were column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: 0.1% NH3H2O IPA; B%: 15% - 15%, flow rate: 100 mL / min.

[0478] LCMS of the first compound: (ESI) m / z = 349.0 [M+H] + , 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.13 - 8.19 (m, 1H) 8.02 - 8.08 (m, 1H) 7.66 - 7.76 (m, 3H) 6.54 (dd, J = 10.38, 7.38 Hz, 1H) 2.90 - 3.03 (m, 1H) 2.78 - 2.88 (m, 1H) 2.62 - 2.68 (m, 1H) 2.54 (br d, J = 2.00 Hz, 1H) 2.48 (s, 3H). SFC chiral analysis: RT = 2.703 min

[0479] LCMS of the second compound: (ESI) m / z = 349.0 [M+H]+ , 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.13 - 8.19 (m, 1H) 8.01 - 8.09 (m, 1H) 7.64 - 7.75 (m, 3H) 6.54 (dd, J=10.32, 7.44 Hz, 1H) 2.90 - 3.03 (m, 1H) 2.78 - 2.89 (m, 1H) 2.62 - 2.68 (m, 1H) 2.54 (br s, 1H) 2.48 (s, 3H). SFC chiral analysis: RT=2.974 min

[0480] Chiral analysis conditions: Column: ChiralPak AS-3 150×4.6 mm I.D., 3 um; Mobile phase: A: CO2 B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4.5 min, then 5% of B for 1.5 min; Flow rate: 2.5 mL / min Column temp.: 40℃; Back pressure: 100 bar

[0481] Synthesis of Compound 68 in Example 24

[0482]

[0483] Step 1: Under nitrogen protection, Zn(CN)2 (68.8 mg, 0.59 mmol) and Pd(PPh3)4 (22.5 mg, 0.2 mmol) were added to a solution of Compound 67-B (60 mg, 0.17 mmol) in NMP (1.2 mL). The mixture was heated to 120℃ and reacted for 16 hours. After the reaction solution was cooled to room temperature, water (5 mL) was added, and it was extracted with EA (5 mL * 3). After conventional post-treatment operation two, a crude product was obtained, and the crude product was purified by prep-HPLC (FA method; B%: 28% - 48%, 13 min) to obtain yellow solid 68-A (17 mg, yield 33%). LCMS: (ESI) m / z=312.1 (M+1) + .

[0484] Step 2: Referring to the method of Step 3 in Example 12, reacting with 68-A (50 mg) gave white solid Compound 68 (12 mg, yield 29.2%). LCMS: (ESI) m / z=253.9 [M+1] + ; 11H NMR (400 MHz, DMSO-d6) δ 11.24 (br s, 1H), 8.25 - 8.34 (m, 1H), 8.18 (br d, J = 8.28 Hz, 1H), 7.67 - 7.80 (m, 2H), 7.06 (s, 1H), 6.43 - 6.52 (m, 1H), 2.83 - 2.98 (m, 1H), 2.70 - 2.82 (m, 2H), 2.28 - 2.42 (m, 1H).

[0485] Synthesis of Compound 73 in Example 25

[0486]

[0487] Step 1: To a solution of 67-A (2.7 g, 10.75 mmol) in DMF (54 mL) was added 3-bromopropene (1.95 g, 16.13 mmol) and K2CO3 (4.46 g, 32.26 mmol). The reaction was carried out at 25 °C for 16 h. After filtration, the mixture was concentrated under reduced pressure. Water (60 mL) was added, and the mixture was extracted with EA (60 mL × 3). After conventional post-treatment operation 2, the crude product was obtained, and the crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 4%) to give off-white solid 73-A (yield 98%). 1 1H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 9.32 (d, J = 8.78 Hz, 1H), 8.33 (d, J = 8.52 Hz, 1H), 7.68 - 7.74 (m, 1H), 7.58 (t, J = 7.64 Hz, 1H), 7.06 (s, 1H), 6.19 (ddt, 1H), 5.54 - 5.61 (m, 1H), 5.45 (dd, J = 1.25, 10.54 Hz, 1H), 4.80 - 4.86 (m, 2H).

[0488] Steps 2 to 3: Referring to the methods of Steps 2 to 3 in Example 12, two-step reaction was carried out with 73-A to give yellow oil compound 73 (two-step yield about 69%). 1 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 7.53 Hz, 1H), 7.97 (d, J = 7.62 Hz, 1H), 7.51 - 7.60 (m, 2H), 6.99 (s, 1H), 6.48 (t, J = 8.91 Hz, 1H), 6.13 - 6.23 (m, 1H), 5.55 (dd, J = 1.25, 17.32 Hz, 1H), 5.41 (dd, J = 1.25, 10.54 Hz, 1H), 4.74 (d, J = 5.27 Hz, 2H), 2.86 - 2.93 (m, 2H), 2.64 - 2.70 (m, 2H).

[0489] Synthesis of Compound 80 in Example 26

[0490]

[0491] Referring to the method in Step 4 of Reference Example 8-b, 67 (70 mg, 227.91 μmol) was reacted with 80-A (1.2 eq) to obtain white solid Compound 80 (25 mg, yield 27%). LCMS: (ESI) m / z = 371.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) 10.57 (s, 1H), 8.67 (s, 1H), 8.27 (d, J = 8.03 Hz, 1H), 7.89 - 7.98 (m, 4H), 7.49 - 7.59 (m, 4H), 7.34 - 7.39 (m, 1H), 6.85 (s, 1H), 6.14 (t, J = 8.78 Hz, 1H), 2.85 - 2.98 (m, 1H), 2.72 - 2.80 (m, 1H), 2.63 - 2.70 (m, 2H)

[0492] Referring to the method of Example 26, the starting materials in the following table were used to replace 80-A for reaction to obtain the corresponding final product compounds.

[0493]

[0494]

[0495]

[0496]

[0497] The synthesis method of starting material 103-A involved in the above table is as follows:

[0498]

[0499] Step 1: To a solution of 103-B (0.7 g, 3.57 mmol) in MeCN (14 mL), 4-tetrahydropyranyl methanesulfonate (4 eq) and cesium carbonate (6 eq) were added. The reaction was carried out at 80 °C for 24 hours. LCMS showed that the reaction was not complete, but the target product was formed. After filtration and concentration under reduced pressure, the crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 5%) to obtain yellow oil 103-C (560 mg, yield 39%). LCMS: (ESI) m / z = 281.9 [M+1] +

[0500] Step 2: Under nitrogen protection, Pd(dppf)Cl2 (104 mg, 0.1 eq) was added to a mixture of compound 103-C (400 mg, 1.43 mmol), bis(pinacolato)diboron (2 eq), and potassium acetate (3 eq) in dioxane (8 mL). The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After completion of the reaction, the temperature was lowered to room temperature, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL * 3). After conventional post-treatment operation 2, the crude product was obtained, and then purified by silica gel column chromatography (EA:PE, EA from 0 to 14%) to obtain yellow solid 103-A (420 mg, 84% yield). (ESI) m / z = 328.1 (M + 1) + .

[0501] The synthetic method of the starting material 101-A involved in the above table is as follows:

[0502]

[0503] At 0 °C, a THF solution (1.3 M, 4.44 mL) of isopropylmagnesium chloride-lithium chloride complex was added dropwise to a THF (20 mL) solution of compound 101-B (1 g, 2.89 mmol). After stirring for 1 hour, a THF (1.18 mL) solution of compound 98-C (1.07 g, 5.78 mmol) was added dropwise. The temperature was raised to 25 °C and stirring was continued for 15 hours. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the mixture was extracted with EA (20 mL × 2). After conventional post-treatment operation 2, it was purified by silica gel column chromatography (EA:PE, EA from 0 to 5%) to obtain off-white solid 101-A (600 mg, 56% yield). LCMS: (ESI) m / z = 347.1 (M + H) + .

[0504] The synthetic method of the starting material 98-A involved in the above table is as follows:

[0505]

[0506] At -70 °C, a THF solution (2.5 M, 1.71 mL) of n-butyllithium was added dropwise to a THF (20 mL) solution of compound 98-B (500 mg, 2.14 mmol). The reaction was stirred for 1 hour under nitrogen protection. Subsequently, compound 98-C (794 mg, 4.27 mmol) was added dropwise, and the temperature was raised to 0 °C and stirred for 3 hours. After completion of the reaction, the reaction was quenched with saturated NH4Cl solution, concentrated under reduced pressure, and EtOAc (20 mL) was added. After filtration, the filtrate was concentrated again under reduced pressure and separated by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain a yellow gum (220 mg, 51.76% yield). 11H NMR (400 MHz, DMSO-d6) Shift 8.72 (s, 1H), 8.67 (d, J = 5.06 Hz, 1H), 7.39 - 7.51 (m, 6H), 1.17 - 1.25 (m, 12H).

[0507] Refer to the method of starting material 98-A, and use the starting materials in the following table to replace 98-B for reaction to obtain the corresponding borate starting materials.

[0508]

[0509] Synthesis of Compound 69 in Example 27

[0510]

[0511] Step 1: Refer to the method of Step 4 in Example 8-b, react 67-B (100 mg) with 18-A (74 mg) to obtain brown solid Compound 69-A (50 mg, yield 47%). LCMS: ES19974-299-P1B1, (ESI) m / z = 367.5 [M+1] +

[0512] Step 2: Refer to the method of Step 3 in Example 12, react Compound 69-A (50 mg) to obtain white solid Compound 69 (1.4 mg, yield 3.28%). LCMS: (ESI) m / z = 309.0 [M+1] + , 1 1H NMR (400 MHz, DMSO-d6) Shift = 10.50 (br s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.91 - 7.84 (m, 2H), 7.58 - 7.51 (m, 2H), 7.51 - 7.45 (m, 1H), 6.76 (s, 1H), 6.09 (dd, J = 7.8, 10.0 Hz, 1H), 3.93 (s, 3H), 2.95 - 2.73 (m, 2H), 2.70 - 2.57 (m, 2H)

[0513] Refer to the method in Example 27, and use the starting materials in the following table to replace 18-A for reaction to obtain the corresponding final product compounds.

[0514]

[0515] Synthesis of Compound 84 in Example 28

[0516]

[0517] Under nitrogen protection, to a mixture of compound 67 (90 mg, 293 μmol), 84-A (100 mg, 352 μmol) in THF / water (2.4 mL, 5 / 1) was added K3PO4 (93.3 mg, 439 μmol) and Pd2(dba)3 (26.8 mg, 29.30 μmol). The mixture was heated to 60 °C and reacted for 16 h. The reaction was diluted with water (5 mL) and extracted with EA (5 mL * 3). After conventional post-treatment operations, a crude product was obtained. The crude product was purified by silica gel thin-layer chromatography (PE:EA, EA from 0 to 15%) and further purified by prep HPLC (FA method; B%: 35% - 55%, 9 min) to obtain white solid compound 84 (18 mg, yield 16%). LCMS: (ESI) m / z = 385.1 [M + 1] +

[0518] Example 28-a Synthesis of Compound 85

[0519]

[0520] Under nitrogen protection, to a mixture of compound 67 (80 mg, 0.26 mmol), 85-A (80 mg, 312 μmol), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (CAS: 1246888-90-3, 17.2 mg, 52.09 umol) and CsF (59.3 mg, 390.70 umol, 14.41 uL, 1.5 eq) in isopropanol (2 mL) was added Pd2(dba)3 (23.8 mg, 26 μmol). The mixture was heated to 50 °C and reacted for 16 h. After cooling to room temperature, the reaction was diluted with water (5 mL) and extracted with EA (5 mL * 3). After conventional post-treatment operations II, a crude product was obtained. The crude product was purified by silica gel thin-layer chromatography (PE:EA, EA from 0 to 25%) and further purified by prep HPLC (FA method, B%: 30% - 50%, 9 min) to obtain white solid compound 85 (10 mg, yield 10.6%). LCMS: (ESI) m / z = 356.0 [M + 1] + . 11H NMR (400 MHz, DMSO-d6) δ 10.77 (br s, 1H), 8.89 (s, 1H), 8.39 (s, 1H), 8.32 (d, J = 7.48 Hz, 1H), 8.11 (dd, J = 4.73, 7.81 Hz, 2H), 7.95 (d, J = 8.36 Hz, 1H), 7.85 (t, J = 7.59 Hz, 1H), 7.68 - 7.74 (m, 1H), 7.55 - 7.66 (m, 2H), 6.80 (s, 1H), 5.80 (br t, J = 8.47 Hz, 1H), 2.58 - 2.81 (m, 4H)

[0521] Synthesis of Compound 74 in Example 29

[0522]

[0523] Step 1: Under nitrogen protection, sodium methanesulfinate (29.3 mg, 287.50 μmol), K3PO4 (81.4 mg, 383.33 μmol), CuI (1.83 mg, 9.58 μmol) and (2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide (2.25 mg, 9.58 μmol) were added to a solution of Compound 67-B (70 mg, 0.19 mmol) in DMSO (1.4 mL). The mixture was heated to 90 °C and reacted for 16 hours. After the reaction solution was cooled to room temperature, EA was added to dilute the reaction, followed by the addition of water (5 mL). The mixture was extracted with EA (10 mL × 3). After conventional post-treatment operations, a crude product was obtained, which was purified by silica gel column chromatography (EA:PE, EA from 0 to 20%) to give a yellow gum 74-A (35 mg, yield 25%). LCMS: (ESI) m / z = 365.0 (M + 1) + .

[0524] Step 2: Referring to the method of Step 3 in Example 12, Compound 74-A (30 mg) was reacted to give a white solid Compound 74 (10 mg, yield 40%). LCMS: (ESI) m / z = 307.0 [M + 1] + , 11H NMR (400 MHz, DMSO-d6) δ 11.23 (br s, 1H), 8.29 - 8.35 (m, 1H), 8.05 - 8.12 (m, 1H), 7.67 - 7.73 (m, 2H), 7.51 (s, 1H), 6.74 (dd, J = 7.53, 10.04 Hz, 1H), 3.44 (br s, 3H), 2.95 (td, J = 10.48, 17.69 Hz, 1H), 2.81 (br dd, J = 8.28, 17.82 Hz, 1H), 2.61 (br d, J = 10.54 Hz, 2H)

[0525] Synthesis of Compound 75 in Example 30

[0526]

[0527] Referring to the methods of Steps 1 to 3 in Example 12: Using 75-A as the starting material for reaction to obtain the yellow solid compound 75-B, and the overall yield of the three steps is about 66.6%. 1 1H NMR (400 MHz, CHLOROFORM-d) Shift = 7.21 - 7.12 (m, 2H), 6.19 (t, J = 8.8 Hz, 1H), 6.07 - 5.91 (m, 1H), 5.47 - 5.30 (m, 2H), 4.54 - 4.52 (m, 2H), 2.78 - 2.71 (m, 2H), 2.59 - 2.54 (m, 2H).

[0528] Step 4: Under nitrogen protection, a mixture of compound 75-B (300 mg, 0.8 mmol), Pd(PPh3)4 (92.2 mg, 79.8 μmol) and morpholine (139.0 mg, 1.60 mmol) in THF (16 mL) was reacted at 20 °C for 16 hours. Water (40 mL) was added, and the mixture was extracted with EA (30 mL × 3). After the conventional post-treatment operation 2, the crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain the white solid compound 75 (125 mg, yield 47%). LCMS: (ESI) m / z = 336.8 [M + 1] + ; 1 1H NMR (400 MHz, DMSO-d6) Shift = 10.58 (s, 1H), 7.20 - 7.03 (m, 2H), 6.09 (t, J = 8.8 Hz, 1H), 2.90 - 2.74 (m, 1H), 2.70 - 2.59 (m, 1H), 2.49 - 2.43 (m, 1H), 2.42 - 2.25 (m, 1H).

[0529] Synthesis of Compound 77 in Example 31

[0530]

[0531] Step 1: To a solution of compound 77-A (1 g, 4.46 mmol) and NIS (1.14 g, 5.07 mmol) in DMSO / ACN (100 mL, 1:1) was added 77-E (65.6 mg, 223.16 μmol), and the reaction was carried out at 25 °C for 15 h. Water (50 mL) was added, and the mixture was extracted with EA (50 mL × 2). After conventional work-up, 1 g of a gray solid was obtained and used directly in the next step. LCMS: (ESI) m / z = 351.8 (M+1) +

[0532] Step 2: Referring to the method of Step 1 in Example 22, reaction was carried out with 77-B (1 g of crude product) to obtain yellow solid compound 77-C (1.1 g, purity 58.65%). LCMS: (ESI) m / z = 409.9 (M+1) +

[0533] Step 3: At -70 °C, a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.3 M, 1.27 mL) was added dropwise to a solution of compound 77-C (560 mg) in THF (30 mL). The temperature was raised to 25 °C and the reaction was stirred for 1 h. At -70 °C, a solution of DMF (120 mg, 1.65 mmol) in THF (1 mL) was added, and the temperature was raised to 25 °C and the reaction was stirred for an additional 0.5 h. The reaction was quenched by adding water (10 mL) at 0 °C, and the mixture was extracted with EA (10 mL × 2). After conventional work-up, purification by silica gel column chromatography (EA:PE, EA from 0 to 5%) gave yellow solid 77-D (240 mg, purity 80.4%). LCMS: (ESI) m / z = 311.9 (M+H) + .

[0534] Steps 4 and 5: Referring to the methods of Steps 2 and 3 in Example 12, two-step reaction was carried out with 77-D to obtain yellow solid compound 77, with an overall yield of 8.8%. LCMS: (ESI) m / z = 310.0 (M+H) + ; 1 H NMR (400 MHz, DMSO-d6) Shift 11.25 (s, 1H), 8.91 (d, J = 4.49 Hz, 1H), 8.54 (d, J = 8.56 Hz, 1H), 7.56 (dd, J = 4.14, 8.41 Hz, 1H), 7.11 - 7.14 (m, 1H), 6.58 (dd, J = 7.53, 8.78 Hz, 1H), 2.71 - 2.91 (m, 2H), 2.57 - 2.68 (m, 2H).

[0535] Synthesis of Compound 86 in Example 32

[0536]

[0537] Step 1: Referring to the method in Step 4 of Example 8-b, react 77-D (200 mg, 644.86 μmol) with 18-A (147 mg, 709.35 μmol) to obtain yellow solid 86-A (130 mg, yield 64.75%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 11.03 (s, 1H), 9.02 (dd, J = 1.83, 4.28 Hz, 1H), 8.58 (dd, J = 1.83, 8.44 Hz, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.44 (dd, J = 4.16, 8.44 Hz, 1H), 7.23 (s, 1H), 5.52 (s, 2H), 3.99 (s, 3H), 3.82 (q, J = 7.09 Hz, 2H), 1.26 (t, J = 7.09 Hz, 3H).

[0538] Step 2 and Step 3: Referring to the methods in Step 2 and Step 3 of Example 12, perform two-step reaction with 86-A (130 mg, 417.56 umol) to obtain yellow solid compound 86 (4 mg), and the overall yield of the two steps is about 2.7%. LCMS: (ESI) m / z = 309.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.85 (dd, J = 1.76, 4.02 Hz, 1H), 8.52 (dd, J = 1.76, 8.28 Hz, 1H), 7.92 (s, 1H), 7.59 (s, 1H), 7.47 (dd, J = 4.27, 8.28 Hz, 1H), 6.84 (s, 1H), 6.10 (t, J = 7.53 Hz, 1H), 3.94 (s, 3H), 2.85 - 2.98 (m, 1H), 2.61 - 2.76 (m, 3H).

[0539] Synthesis of Compounds 92, 93, and 94 in Example 33

[0540]

[0541] Step 1: Under nitrogen protection, add Pd(OAc)2(26.8mg, 119.68μmol), hexacarbonyl molybdenum (Mo(CO)6, 173mg, 658.25μmol) and tri-tert-butylphosphine tetrafluoroborate (34.7mg, 119.68μmol) to a solution of compound 67-B (370mg, 1.20mmol) and DBU (273mg, 1.80mmol) in EtOH (10mL). React at 90°C for 16 hours under nitrogen protection. Filter and distill under reduced pressure to remove the solvent, and purify by silica gel column chromatography (EA:PE, EA from 0 to 2%) to obtain yellow oil compound 92-A (170mg, yield 47%). LCMS: (ESI) m / z=303.0 (M+1) + .

[0542] Step 2 and Step 3: Referring to the method of Step 2 and Step 3 in Example 12, 92-A (260 mg, 860 μmol) was used for two-step reaction to obtain white solid compound 92 (40 mg), with a two-step yield of about 15.5%. LCMS: (ESI) m / z=301.3 (M+1) + . 1 H NMR (400MHz, CDCl3) δ8.35-8.50(m,1H),7.90-8.06(m,1H),7.59-7.77(m,2H),7.36(br s,1H),7.30(s,1H),5.90(dd,J=2.31,8.47Hz,1H),3.91-4.26(m,2H),2.77-2.93(m,1H),2.59-2. 73(m,1H),2.46(td,J=6.27,16.95Hz,1H),2.03(dt,J=6.71,14.36Hz,1H),1.25(t,J=7.15Hz,3H).

[0543] Step 4: Compound 92 (20 mg) was dissolved in THF (0.3 mL), and NaOH (10.7 mg, 266 μmol) aqueous solution (0.3 mL) was added and stirred at 25 °C for 2 hours. The reaction solution was adjusted to pH 2 with 1 M HCl solution, and the mixture was extracted with EA (1 mL × 3). The crude product was concentrated under reduced pressure. The crude product was ground and slurried with DCM (3 mL) for 10 minutes, and filtered to obtain a white solid compound 93 (15 mg, yield 82.48%). 11H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H), 10.95 (br s, 1H), 8.22 - 8.42 (m, 1H), 7.99 - 8.16 (m, 1H), 7.54 - 7.88 (m, 2H), 7.04 (s, 1H), 5.97 (dd, J = 2.53, 8.25 Hz, 1H), 2.55 - 2.71 (m, 1H), 2.33 - 2.47 (m, 1H), 2.14 - 2.29 (m, 1H), 1.83 - 1.98 (m, 1H). LCMS: (ESI) m / z = 273.2 (M+1) + .

[0544] Step 5: To a solution of compound 93 (40 mg, 146.92 μmol) and HOBT ammonium salt (CAS: 63307 - 62 - 0, 111.77 mg, 734.61 μmol) in DMF (1 mL), add DIEA (56.96 mg, 440.77 umol) and HATU (139.66 mg, 367.31 μmol), and stir at 25 °C for 2 h. Dilute with water (2 mL) and acetonitrile (1 mL), and filter. The filtrate is concentrated and purified by prep HPLC (column: C18 - 1 150*30mm*5um; mobile phase: [water(FA) - ACN]; B%: 5% - 45%, 9 min) to obtain white solid compound 94 (20 mg, yield 50.18%). 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.25 - 8.40 (m, 1H), 8.04 - 8.17 (m, 1H), 7.64 - 7.83 (m, 2H), 7.35 (br s, 1H), 7.03 (s, 1H), 6.82 (brs, 1H), 5.95 (dd, J = 2.64, 7.92 Hz, 1H), 2.55 - 2.72 (m, 1H), 2.18 - 2.33 (m, 1H), 1.95 - 2.06 (m, 1H), 1.80 - 1.95 (m, 1H). LCMS: (ESI) m / z = 272.0 (M+1) + .

[0545] Synthesis of Compound 117 in Example 34

[0546]

[0547] To a mixture of compound 116 (100 mg, 0.33 mmol) in THF (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (20.5 mg, 0.49 mmol, about 1.5 eq.). The reaction was carried out at 25 °C for 16 h. THF was removed by distillation under reduced pressure, and the pH was adjusted to 6 - 7 with AcOH. Separation by prep HPLC (FA method, B: 18% - 38%, 10 min) gave a white solid (25 mg, yield 25.68%). 1 H NMR (400 MHz, DMSO-d6) Shift 10.84 (m, 1H), 9.38 - 12.31 (m, 1H), 6.82 - 7.05 (m, 1H), 6.42 - 6.56 (m, 1H), 5.73 (d, J = 4.65 Hz, 0.24H), 5.37 (s, 0.76H), 3.67 - 3.82 (m, 3H), 2.64 - 2.75 (m, 2H), 2.38 - 2.43 (m, 2H), 2.21 (dt, J = 2.45, 5.69 Hz, 2H), 1.29 (dt, J = 4.46, 8.16 Hz, 1H), 1.05 (br d, J = 4.52 Hz, 1H), 0.68 - 0.99 (m, 1H). LCMS: (ESI) m / z = 293.3 (M + 1) +

[0548] Synthesis of Compounds 118 and 119 in Example 35

[0549]

[0550] A solution of compound 117 (90 mg, 307.92 μmol) in TFA (0.2 mL) and DCM (2 mL) was stirred at 25 °C for 1 h. The reaction was quenched with saturated NaHCO3 solution (5 mL), and extracted with DCM (5 mL * 3). After conventional work-up, a yellow oil 117-A (60 mg, yield 71.05%) was obtained. LCMS: (ESI) m / z = 275.3 (M + 1) +

[0551] Compound 117-A (15 mg) was purified by prep HPLC (column: Boston Prime C18 150 * 30 mm * 5 um; mobile phase: [water (ammonia hydroxide v / v) - ACN]; gradient: 33% - 53% B over 10 min) to give white solid compound 118 (8 mg, purity 80%) and white solid compound 119 (5 mg, purity 90%).

[0552] Compound 118: 1 H NMR(400MHz,DMSO-d6)Shift 7.15(s,1H),6.86(s,1H),5.48(s,1H),3.83(s,3H),2.89 - 2.98(m,2H),2.75 - 2.83(m,2H),2.16 - 2.38(m,3H),1.30 - 1.37(m,1H),1.00 - 1.06(m,1H). LCMS:(ESI)m / z=275.3(M + 1) +

[0553] Compound 119: 1 H NMR(400MHz,DMSO-d6)Shift 7.06(s,1H),6.77 - 6.86(m,1H),6.83(s,1H),5.80(d,J=4.52Hz,1H),3.84(s,3H),2.89 - 2.95(m,2H),2.73 - 2.81(m,2H),2.58 - 2.66(m,1H),2.21(ddd,J=3.14,5.58,8.85Hz,1H),1.06(dt,J=4.89,8.22Hz,1H),0.70(q,J=4.27Hz,1H). LCMS:(ESI)m / z=275.3(M + 1) +

[0554] Synthesis of Compound 25 in Example 36

[0555]

[0556] Step 1: Referring to the method of Step 6 in Example 1, react (14 - c - 1)(1.5g, 6.29mmol) with Compound 25 - A(860mg, 2.67mmol) to obtain white solid Compound 25 - B(70mg, yield 2.9%). (ESI)m / z=377.1(M + 1) + .

[0557] Step 2: Add ammonium fluoride(11.8mg, 318.67umol, 2eq) to a MeOH(2mL) solution of Compound 25 - B(60mg, 159μmol), and react at 25℃ for 2 hours. After completion of the reaction, concentrate under reduced pressure, add EtOAc(20mL), and purify by silica gel column chromatography(EA / PE, EA from 0 to 50%) after conventional post - treatment operation two to obtain white solid Compound 25(5mg, yield 14.25%).(ESI)m / z=221.0(M + 1) + . 11H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 8.03 Hz, 1H), 6.46 (d, J = 2.26 Hz, 1H), 6.39 - 6.44 (m, 1H), 5.50 (s, 1H), 3.82 (s, 3H), 2.25 (m, 1H), 2.14 - 2.21 (m, 1H), 1.33 (m, 1H), 1.02 - 1.10 (m, 1H).

[0558] Synthesis of Compound 134 in Example 37

[0559]

[0560] Acetic anhydride (14.7 mg, 144.09 μmol) was added to a solution of compound 134-A (20 mg, 96 μmol) in pyridine (0.5 mL). The reaction was carried out at room temperature (15 °C) for 16 h. The reaction mixture was concentrated under reduced pressure, water (2 mL) was added, and the mixture was extracted with EA (1 mL × 2). After conventional post-treatment operations, the crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE, EA from 0 to 30%) to give yellow oil 134 (15 mg, yield 60.28%). LCMS: ESI m / z = 251.0 [M + H] + . 1 1H NMR (400 MHz, CDCl3) δ ppm 7.34 (d, J = 8.44 Hz, 1H) 6.73 (dd, J = 8.31, 2.08 Hz, 1H) 6.68 (d, J = 2.08 Hz, 1H) 5.74 (t, J = 7.03 Hz, 1H) 3.85 (s, 3H) 2.67 - 2.76 (m, 1H) 2.60 - 2.66 (m, 2H) 2.33 (s, 3H) 2.09 - 2.20 (m, 1H).

[0561] Referring to the method in Example 37, the starting materials in the following table were used to replace 134-A for the reaction to obtain the corresponding final compounds.

[0562]

[0563]

[0564] Referring to the method in Example 37, the starting materials in the following table were used for the reaction to obtain the corresponding final compounds.

[0565]

[0566] Synthesis of Compound 138 in Example 38

[0567]

[0568] To a solution of compound 67 (50 mg, 163 μmol) in DCM (2 mL) was added TEA (24.7 mg, 212 μmol) and benzoyl chloride (29.7 mg, 212 μmol). The reaction was carried out at 25 °C for 4 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE, EA from 0 to 30%) to obtain white solid compound 138 (20 mg, yield 28.6%). LCMS: (ESI) m / z = 411.0 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 7.28 Hz, 2H), 8.20 (d, J = 8.53 Hz, 1H), 8.00 (d, J = 8.03 Hz, 1H), 7.91 (s, 1H), 7.81 - 7.87 (m, 1H), 7.66 - 7.77 (m, 4H), 6.58 (dd, J = 7.53, 10.29 Hz, 1H), 2.80 - 3.06 (m, 2H), 2.64 - 2.75 (m, 1H), 2.55 - 2.62 (m, 1H).

[0569] Referring to the method of Example 38, the starting materials in the following table were used to replace benzoyl chloride and reacted with compound 67 to obtain the corresponding final product compounds.

[0570]

[0571] Synthesis of compounds 140 and 141 in Example 39

[0572]

[0573] Step 1: To a solution of compound 67 (50 mg, 163 μmol) and compound 141-A (38.5 mg, 179 μmol, 1.1 eq) in DCM (2 mL) was added EDCI (40.5 mg, 211.63 μmol, 1.3 eq) and DMAP (1.99 mg, 16.28 μmol, 0.1 eq). The mixture was stirred at 25 °C for 3 h and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE, EA from 0 to 30%) to obtain white solid compound 141 (70 mg, yield 82%). 11H NMR (400 MHz, DMSO-d6) δ 8.09 - 7.95 (m, 2H), 7.60 - 7.81 (m, 3H), 6.54 (br dd, J = 7.64, 9.96 Hz, 1H), 4.52 - 4.77 (m, 1H), 3.46 - 3.56 (m, 2H), 2.62 - 3.06 (m, 3H), 2.44 (br d, J = 5.14 Hz, 3H), 1.90 - 2.16 (m, 2H), 1.44 (d, J = 18.46 Hz, 9H). (ESI) m / z = 403.9 [M - Boc + H] +

[0574] Step 2 (Representative method for removing Boc protecting group): A solution of compound 141 (20 mg, 0.397 mmol) in DCM (2 mL) and TFA (0.4 mL) was stirred at 25 °C for 2 hours, concentrated under reduced pressure, and the resulting residue was purified by prep HPLC (FA method; B%: 5% - 35%, 8 min) to obtain white solid compound 140 (2 mg, yield 12%). LCMS: (ESI) m / z = 404.1 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 7.78 Hz, 1H), 7.96 (d, J = 8.53 Hz, 1H), 7.50 - 7.69 (m, 2H), 7.11 (s, 1H), 6.43 (dd, J = 7.53, 10.29 Hz, 1H), 3.67 (br dd, J = 6.02, 8.53 Hz, 1H), 2.74 - 3.07 (m, 4H), 1.65 - 2.13 (m, 4H).

[0575] Referring to the method of Step 1 in Example 39, the starting materials in the following table were used to replace 141-A and reacted with compound 67 to obtain the corresponding final compounds.

[0576]

[0577]

[0578] Referring to the method of Step 1 in Example 39, the starting materials in the following table were used for reaction to obtain the corresponding final compounds.

[0579]

[0580]

[0581] Synthesis of Compound 161 in Example 40

[0582]

[0583] Step 1: Referring to the method of Example 38, using compound 76 (60 mg) and compound 161-A (5 eq) as starting materials to carry out the reaction to obtain yellow solid compound 161-B (100 mg). The crude product was directly used for the next reaction.

[0584] Step 2: Referring to the method of Step 2 in Example 39, using compound 161-B (100 mg) to carry out the reaction to obtain white solid compound 161 (25 mg, the overall yield of two steps is about 29%). LCMS: (ESI) m / z = 398.1 (M+1) + , 1 H NMR (400 MHz, DMSO-d6) Shift 8.46 (br s, 2H), 8.30 - 8.36 (m, 1H), 8.24 (dd, J = 2.87, 7.03 Hz, 1H), 8.16 (d, J = 8.44 Hz, 1H), 7.52 - 7.83 (m, 4H), 6.41 (s, 0.86H), 6.28 (s, 0.12H), 2.54 - 2.70 (m, 2H), 1.39 - 1.68 (m, 2H).

[0585] Synthesis of Compound 143 in Example 41

[0586]

[0587] Add DIEA (84.9 mg, 657 μmol) and trichlorosilane (89.0 mg, 657 μmol) to a solution of compound 142 (100 mg, 0.22 mmol) in DCM (2 mL). Stir the reaction at 25 °C for 2 hours. Quench the reaction with saturated NaHCO3 solution (10 mL), and extract the mixture with DCM (15 mL × 3). After the conventional post-treatment operation 2, a residue was obtained, and the residue was purified by silica gel column chromatography (EA: PE, EA from 0 to 40%) to obtain white solid compound 143 (30 mg, yield 28%). LCMS: (ESI) m / z = 427.9 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.53 Hz, 1H), 8.09 - 8.15 (m, 1H), 7.93 - 7.97 (m, 1H), 7.81 (s, 1H), 7.65 - 7.75 (m, 2H), 7.39 - 7.45 (m, 1H), 6.90 (d, J = 8.53 Hz, 1H), 6.78 - 6.84 (m, 2H), 6.69 (t, J = 7.53 Hz, 1H), 6.57 (dd, J = 7.28, 10.29 Hz, 1H), 2.79 - 3.06 (m, 2H), 2.65 - 2.74 (m, 1H), 2.57 - 2.61 (m, 1H).

[0588] Synthesis of Compound 149 in Example 42

[0589]

[0590] To a solution of Compound 149-A (36.7 mg, 146 μmol) and thionyl chloride (20.9 mg, 176 μmol) in DCM (0.2 mL) was added 1 drop of DMF, and the mixture was stirred at 40 °C for 40 minutes. After cooling to 25 °C, the solvent was evaporated to dryness under nitrogen. Then a solution of Compound 67 (30 mg, 97.68 μmol) in pyridine (2 mL) was added, and the mixture was stirred at 60 °C for 1 hour. EtOAc (4 mL) was added, and after the conventional post-treatment operation II, a crude product was obtained. The crude product was purified by silica gel column chromatography (EA / PE, EA from 8% to 30%) to give white solid Compound 149 (25 mg, yield 47%). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 - 2.59 (m, 1H) 2.68 - 2.74 (m, 1H) 2.83 - 2.89 (m, 1H) 2.92 - 3.00 (m, 1H) 4.03 (s, 6H) 6.57 (dd, J = 10.27, 7.46 Hz, 1H) 7.15 (s, 1H) 7.68 (s, 1H) 7.74 - 7.81 (m, 2H) 8.15 - 8.19 (m, 1H) 8.20 - 8.26 (m, 1H). LCMS: (ESI) m / z = 541.0 (M + 1) + .

[0591] Synthesis of Compound 160 in Example 43

[0592]

[0593] To a solution of compound 76 (65 mg, 204 μmol) and cesium carbonate (99.5 mg, 305.50 μmol) in DMF (2 mL) was added compound 160-A (38 mg, 306 μmol), and the reaction was carried out at 25 °C for 16 h. After completion of the reaction, saturated brine (10 mL) was added, and the mixture was extracted with EtOAc (5 mL * 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EA / PE, EA from 0 to 20%), and then further purified by prep HPLC (FA method; B%: 43% - 63%, 16 min) to obtain white solid compound 160 (10 mg, yield 12%). (ESI) m / z = 407.2 (M + 1) + . 1 H NMR (400 MHz, CDCl3), δ 8.22 - 8.40 (m, 1H), 8.09 (d, J = 8.58 Hz, 1H), 7.48 - 7.69 (m, 2H), 7.33 (s, 1H), 6.33 (s, 1H), 5.99 (s, 2H), 3.87 (s, 3H), 2.50 - 2.67 (m, 1H), 2.42 (dt, J = 4.62, 6.05 Hz, 1H), 1.62 - 1.66 (m, 1H), 1.37 (q, J = 4.03 Hz, 1H).

[0594] Synthesis of Compound 163 in Example 44

[0595]

[0596] Step 1:

[0597] Preparation of LDA solution: At -78 °C, a solution of n-butyllithium in THF (2.5 M, 1.46 mL) was added dropwise to a solution of diisopropylamine (402 mg, 3.98 mmol) in THF (8 mL), and the mixture was stirred at 20 °C for 0.5 h.

[0598] At -20 °C, a solution of compound 163-A (400 mg, 1.66 mmol) in THF (2 mL) was added to the above LDA solution, and the mixture was stirred at 0 °C for 1 h. Subsequently, tert-butyl bromoacetate (356 mg, 1.83 mmol) and 1,3-dimethyl-2-imidazolidinone (189 mg, 1.66 mmol) were added, and the mixture was stirred at 0 °C for 5 h. The reaction was quenched with saturated NH4Cl solution (6 mL). After stirring at 20 °C for 0.5 h, the mixture was extracted with EtOAc (8 mL x 3), and after conventional post-treatment operations, the crude product was obtained and purified by silica gel column chromatography (EA / PE, EA from 8 to 32%) to obtain yellow oil 163-B (161 mg, yield 27.32%). 11H NMR (400 MHz, DMSO-d6) δ ppm 1.36 - 1.40 (m, 9H) 1.75 - 1.85 (m, 1H) 2.00 - 2.06 (m, 1H) 2.34 - 2.43 (m, 1H) 2.54 - 2.57 (m, 1H) 2.81 - 2.92 (m, 2H) 2.96 - 3.04 (m, 1H) 6.66 - 6.70 (m, 1H) 6.94 - 7.00 (m, 1H) 10.63 - 10.70 (m, 1H).

[0599] Step 2: A solution of compound 163-B (140 mg, 394.12 μmol) in DCM (2 mL) and TFA (224 mg, 1.97 mmol, 150 μL, 5 eq) was reacted at 40 °C for 1 h. Concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE, EA from 0 to 57%) to obtain yellow oil 163-C (51 mg, yield 43%). LCMS: (ESI) m / z = 300.9 [M+H] + .

[0600] Step 3: Referring to the method of Step 2 in Example 5, the reaction was carried out with compound 163-C (45 mg, 150.4 μmol) to obtain white solid compound 163 (12 mg, yield 28.2%). 1 1H NMR (400 MHz, CDCl3) δ ppm 1.86 (br dd, J = 13.27, 3.97 Hz, 1H) 2.43 (d, J = 17.36 Hz, 1H) 2.65 - 2.85 (m, 4H) 2.97 (dd, J = 17.18, 7.52 Hz, 1H) 5.03 - 5.22 (m, 1H) 5.54 (d, J = 5.26 Hz, 1H) 6.61 (d, J = 2.45 Hz, 1H) 7.04 (d, J = 2.45 Hz, 1H). LCMS: (ESI) m / z = 284.9 (M+1) + .

[0601] Synthesis of Compounds 164 and 165 in Example 45

[0602]

[0603] Step 1: Aluminum trichloride (3.24 g, 24.32 mmol) was added to a solution of compound 164-A (2.01 g, 16.22 mmol) in DCM (50 mL). After stirring at 10 °C for 10 minutes, a solution of 164-B (2.5 g, 16.22 mmol) in DCM (5 mL) was added dropwise. After stirring at 10 °C for 10 minutes, the reaction mixture was refluxed for 3 hours. The mixture was concentrated under reduced pressure, water (100 mL) was added, and the pH was adjusted to 1 - 2 with concentrated hydrochloric acid. The mixture was extracted with DCM (100 mL × 3). After conventional work-up, the crude product was obtained and purified by silica gel column chromatography (EA / PE, EA from 16 to 53%) to give yellow solid 164-C (180 mg, yield 4%). 1 H NMR (400 MHz, DMSO-d6) 11.95 (br s, 1H), 10.18 (s, 1H), 7.36 (d, J = 7.96 Hz, 1H), 6.44 (s, 1H), 6.40 (dd, J = 2.26, 8.53 Hz, 1H), 3.82 (s, 3H), 3.67 (br d, J = 4.02 Hz, 1H), 2.68 (br s, 1H), 1.62 - 1.93 (m, 6H), 1.49 (br s, 1H), 1.34 (br d, J = 15.06 Hz, 4H)

[0604] Step 2: Referring to the method of Step 2 in Example 5, compound 164-C (100 mg, 359.3 μmol) was reacted (NaOH was 5 eq, NaBH4 was 40 eq) to give white solid compound 164 (18 mg, yield 19.1%) and white solid compound 165 (8 mg, yield 8.5%).

[0605] Compound 164: LCMS: (ESI) m / z = 263.0 [M + 1] + ; 11H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 0.6H), 9.47 (s, 0.3H), 7.02 (d, J = 8.0 Hz, 0.3H), 6.93 (d, J = 8.3 Hz, 0.6H), 6.45 (d, J = 2.0 Hz, 0.6H), 6.42 (d, J = 2.0 Hz, 0.3H), 6.36 (dd, J = 8.3, 2.0 Hz, 1H), 5.53 (d, J = 4.5 Hz, 0.3H), 5.29 (d, J = 3.5 Hz, 0.6H), 3.77 (s, 2H), 3.75 (s, 1H), 3.10 (br t, J = 5.6 Hz, 0.3H), 2.65 - 2.72 (m, 1.2H), 2.35 - 2.43 (m, 0.6H), 1.98 (br d, J = 14.1 Hz, 0.4H), 1.77 - 1.88 (m, 1.3H), 1.42 - 1.63 (m, 3.2H), 1.16 - 1.30 (m, 2H), 0.83 - 1.05 (m, 1.2H), 0.58 - 0.69 (m, 0.3H)

[0606] Compound 165: LCMS: (ESI) m / z = 263.0 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.44 (s, 1H), 6.39 (br d, J = 8.3 Hz, 1H), 5.33 (d, J = 10.3 Hz, 1H), 3.74 (s, 3H), 2.31 - 2.39 (m, 1H), 1.92 - 2.04 (m, 2H), 1.66 - 1.82 (m, 2H), 1.61 (br d, J = 12.0 Hz, 1H), 1.14 - 1.30 (m, 4H)

[0607] Synthesis of Compound 166 in Example 46

[0608]

[0609] Step 1: Referring to the method of the representative operation of catalytic hydrogenation, using compound 166-A (35 mg) as the raw material, a white solid compound 166 (28 mg, yield 39%) was obtained. Purified by silica gel column chromatography (EA:PE, EA from 0 to 25%). LCMS: (ESI) m / z = 291.1 [M+1] + ; 11H NMR (400 MHz, CDCl3) δ 6.99 (s, 1H), 6.58 (s, 1H), 5.40 (s, 1H), 3.92 (s, 1H), 3.77 (s, 3H), 2.84 - 2.93 (m, 2H), 2.67 - 2.80 (m, 2H), 1.60 (s, 3H).

[0610] Synthesis of Compound 168: To a solution of Compound 166 in DMF (0.5 mL) was added NaOH (0.5 M, 1.5 eq). The reaction was stirred at 25 °C for 2 h. LCMS showed that 20% of the starting material remained and 35% of the target product was formed. The pH was adjusted to 6 with formic acid and the product was directly purified by prep HPLC (FA method - B; B%: 23% - 43%, 10 min) to give Compound 168 as a white solid (yield 54%). LCMS: (ESI) m / z = 309.0 [M + 1] + ; 1 1H NMR (400 MHz, DMSO - d6) δ 9.67 - 11.99 (m, 1H), 7.06 (br s, 1H), 6.50 (br s, 1H), 5.37 (br s, 1H), 4.29 (br s, 1H), 3.76 (br s, 1H), 3.69 (br s, 3H), 2.61 - 2.79 (m, 2H), 2.44 (br d, J = 7.03 Hz, 2H), 1.49 - 1.63 (m, 3H).

[0611] Synthesis of Compound 167: Referring to the synthesis method of Example 5 - a, Compound 166 was reacted with methylamine (33% ethanol solution) (reaction time 2 h, 44% of the starting material remained) to give Compound 167 as a white solid, with a yield of 28.4%. LCMS: (ESI) m / z = 322.0 [M + 1] + ; 1 1H NMR (400 MHz, DMSO - d6) δ 9.84 (br s, 1H), 7.75 (br s, 1H), 7.02 (s, 1H), 6.49 (s, 1H), 5.37 (s, 1H), 4.29 (s, 1H), 3.70 (s, 3H), 2.63 - 2.71 (m, 2H), 2.56 (br d, J = 4.28 Hz, 3H), 2.24 - 2.32 (m, 2H), 1.58 (s, 3H).

[0612] Synthesis of Compound 169 in Example 47

[0613]

[0614] To a mixture of compound 169-A (100 mg, 416 μmol) in THF (2 mL) and water (5 mL) were added NaOH (49.9 mg, 1.25 mmol) and NaBH4 (94.5 mg, 2.5 mmol). The reaction was stirred at 20 °C for 3 h. At 10 °C, 1 M HCl (5 mL) and EtOAc (5 mL) were added, and the mixture was extracted with EA (5 mL × 2). The combined organic phases were dried under nitrogen (Note: Do not concentrate under reduced pressure) to obtain the crude product, which was purified by silica gel column chromatography (EA / PE, EA from 0 to 50%) to give white compound 169 (20 mg, yield 21%). LCMS: (ESI) m / z = 224.9 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 7.78 Hz, 1H), 6.88 (d, J = 1.51 Hz, 1H), 6.85 (dd, J = 1.51, 7.78 Hz, 1H), 5.03 (br s, 1H), 4.79 (dd, J = 4.64, 7.15 Hz, 1H), 3.74 (s, 3H), 2.15 - 2.23 (m, 2H), 1.64 - 1.85 (m, 2H).

[0615] Synthesis of Compound 171 and Compound 267 in Example 48

[0616]

[0617] Step 1: Referring to the method in Step 1 of Example 45, 164-A (9.5 g, 76.53 mmol) was reacted with 171-B (1 eq) to obtain yellow solid 171-A (130 mg, yield 0.68%) and yellow oil 267-A (14 g, 55.9 mmol, yield 73.1%).

[0618] Compound 171-A: 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.63 (s, 1H), 7.46 (s, 1H), 7.43 - 7.45 (m, 1H), 6.32 - 6.39 (m, 2H), 3.5 (s, 3H), 1.75 (s, 3H), 1.58 (s, 3H).

[0619] Synthesis of Compound 171: Dissolve Compound 171-A (50 mg, 199 μmol) in THF (5 mL), add palladium hydroxide / carbon (20% content, 100 mg), and the reaction mixture is thoroughly purged with hydrogen. Stir the reaction at 25 °C for 16 hours under a hydrogen atmosphere of 15 Psi. Filter the reaction solution by suction, concentrate it to dryness under reduced pressure, and purify it by silica gel column chromatography (EA / PE, EA from 0 to 35%) to obtain yellow solid Compound 171 (15 mg, yield 32%). 1 H NMR (400HMz, DMSO-d6) δ (ppm) 9.59 (s, 1H), 6.96 - 7.01 (m, 1H), 6.35 - 6.44 (m, 2H), 5.22 - 5.39 (m, 1H), 3.75 (s, 3H), 2.68 - 2.85 (m, 1H), 2.49 - 2.55 (m, 1H), 1.05 - 1.18 (m, 3H), 0.94 - 1.03 (m, 2H), 0.36 - 0.38 (m, 0.5H). LC-MS: (ESI) m / z. [M+H] + 237.0.

[0620] Synthesis of Compound 267: Refer to the synthesis method of Compound 171, and react with Compound 267-A (100 mg, 399 μmol, 1 eq) to obtain white solid Compound 267 (30 mg, yield 30.5%). 1 H NMR (400HMz, DMSO-d6) δ (ppm) 9.72 - 9.92 (m, 1H), 6.97 - 7.13 (m, 1H), 6.42 (dt, J = 2.2, 4.7 Hz, 2H), 5.20 - 5.69 (m, 1H), 3.70 (s, 3H), 2.82 - 3.20 (m, 1H), 2.56 - 2.80 (m, 1H), 1.07 (dd, J = 7.4, 15.7 Hz, 3H), 0.36 - 0.98 (m, 3H). LC-MS: (ESI) m / z. [M+H] + 237.0。

[0621] Synthesis of Compound 174 in Example 50

[0622]

[0623] Step 1: A mixture of compound 174-A (100 mg, 485 μmol), morpholine (123 mg, 1.45 mmol, 3 eq), and glyoxylic acid (179 mg, 1.21 mmol, 135 μL, 2.5 eq) was stirred at 60 °C for 16 h. After cooling to room temperature, it was diluted with 5 ACN (1 mL) and purified directly by prep HPLC (FA method, B: 15%-35% B over 38 min) to obtain brown solid compound 174-B (38 mg, yield 22.4%). 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.87 (d, J = 8.6 Hz, 1H), 6.58 (dd, J = 2.4, 8.8 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 6.03 - 6.20 (m, 1H), 5.47 (dd, J = 1.3, 17.4 Hz, 1H), 5.38 (dd, J = 0.9, 10.6 Hz, 1H), 4.66 (d, J = 5.7 Hz, 2H), 4.21 (t, J = 6.2 Hz, 1H), 3.88 (s, 3H), 3.80 - 3.85 (m, 4H), 3.65 - 3.74 (m, 1H), 3.47 - 3.57 (m, 1H), 2.81 - 2.88 (m, 4H).

[0624] Step 2: Referring to the method in Step 2 (representative operation for constructing a five-membered lactone ring) of Example 5, compound 174-B (310 mg, 887 μmol, 1 eq) was reacted to obtain yellow oil 174-C (77 mg, 230 μmol, yield 26%). LC-MS: (ESI) m / z. [M+H] + 334.1.

[0625] Step 3: Referring to the method in Step 3 of Example 2, compound 174-C (77 mg, 230 μmo) was reacted to obtain a white solid compound (15 mg, 51 μmol, yield 22.1%). 11H NMR (400 MHz, DMSO-d6) δ (ppm) 9.68 - 10.17 (m, 1H), 7.05 - 7.22 (m, 1H), 6.42 (dd, J = 2.1, 4.5 Hz, 2H), 5.61 (dd, J = 5.0, 8.5 Hz, 0.3H), 5.51 (dd, J = 5.7, 10.8 Hz, 0.7H), 3.91 (dd, J = 8.4, 12.1 Hz, 0.7H), 3.69 - 3.76 (s, 3H), 3.67 (dd, J = 2.3, 4.7 Hz, 0.3H), 3.59 (t, J = 4.5 Hz, 4H), 2.76 - 2.91 (m, 2H), 2.42 - 2.50 (m, 3H), 2.18 - 2.39 (m, 1H). LC-MS: (ESI) m / z. [M + H] + 294.1.

[0626] Synthesis of Compound 271 and Compound 272 in Example 51

[0627]

[0628] Step 1: At 0 °C, 271-B (500 mg, 3.94 mmol) was added to a mixture of Compound 271-A (500 mg, 3.49 mmol) and Na2CO3 (740 mg, 6.98 mmol) in THF / water (10 mL, 1:1). The mixture was reacted at 0 °C for 10 minutes. The solvent was removed under reduced pressure, and the crude product was separated and purified by Prep HPLC (column: C18 150×40 mm; mobile phase: [water (FA) - ACN]; gradient: 1% - 41% B over 9 min) to obtain a colorless oil, 271-C (520 mg, yield 64%). LCMS: (ESI) m / z = 234.0 (M + 1) + .

[0629] Step 2:

[0630] Preparation of acyl chloride: Thionyl chloride (349 mg, 2.01 eq) and DMF (1.00 mg, 0.01 eq) were added to a solution of Compound 271-C (320 mg, 1.37 mmol) in DCM (5 mL). After stirring at 25 °C for 2 hours, the mixture was concentrated under reduced pressure and dissolved in THF (2 mL) for later use.

[0631] To a mixture of compound 271-D (140 mg, 687 μmol) in THF / water (10 mL, 1:1) was added Na2CO3 (218 mg, 2.06 mmol), and the temperature was lowered to 0 °C. The acyl chloride solution prepared above was added thereto, and the mixture was stirred at 0 °C for 10 minutes. The mixture was concentrated under reduced pressure, and the crude product was directly purified by prep HPLC (column: Boston Prime C18

[0632] 150*30 mm*5 um; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 10%-30% B over 10 min) to obtain yellow solid compound 271-E (110 mg, yield 38.29%). LC-MS:

[0633] (ESI) m / z. [M+H] + 420.3.

[0634] Step 3: Referring to the method in Step 2 of Example 39 (a representative method for removing the Boc protecting group), compound 271-E (110 mg) was reacted to obtain white solid compound 271-F (80 mg, 184 μmol, yield 70.40%, TFA salt). LC-MS: (ESI) m / z. [M+H] + 320.0.

[0635] Step 4: To a solution of compound 271-F (70 mg, 161.36 μmol, 1 eq, TFA) in DMF (1 mL) were added DIEA (104 mg, 806 μmol, 5 eq) and compound 112 (42.3 mg, 161 μmol, 1.0 eq), and the mixture was stirred at 50 °C for 16 hours. The reaction solution was directly purified by prep HPLC (FA method, B: 18%-38% over 11 min) to obtain white solid compound 271 (15 mg, 26.4 μmol, yield 16.36%) and white solid compound 272 (45 mg, 74.2 μmol, yield 46.00%).

[0636] Compound 271: 11H NMR (400 MHz, DMSO-d6) δ (ppm) 9.45 - 9.78 (m, 1H), 7.74 - 8.05 (m, 2H), 6.99 (d, J = 3.9 Hz, 1H), 6.77 (br dd, J = 10.7, 16.3 Hz, 1H), 6.48 (s, 1H), 6.06 (dd, J = 2.3, 16.8 Hz, 1H), 5.48 - 5.73 (m, 2H), 3.78 - 4.50 (m, 4H), 3.72 (s, 3H), 2.78 - 3.13 (m, 3H), 2.63 - 2.75 (m, 3H), 2.40 - 2.46 (m, 1H), 2.31 - 2.39 (m, 2H), 1.89 - 2.24 (m, 4H), 1.42 - 1.89 (m, 4H), 1.04 - 1.38 (m, 2H). LC-MS: (ESI) m / z. [M+H] + 546.3

[0637] Compound 272: 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.35 - 9.86 (m, 1H), 7.97 - 8.11 (m, 1H), 7.80 - 7.96 (m, 1H), 6.99 (d, J = 4.0 Hz, 1H), 6.49 (s, 1H), 5.59 (t, J = 7.5 Hz, 1H), 4.72 - 4.81 (m, 1H), 4.00 - 4.39 (m, 2H), 3.64 - 3.86 (m, 6H), 2.61 - 3.06 (m, 8H), 2.29 - 2.48 (m, 4H), 1.88 - 2.28 (m, 4H), 1.42 - 1.87 (m, 4H), 1.08 - 1.41 (m, 2H). LC-MS: (ESI) m / z. [M+H] + 582.5

[0638] Referring to the synthesis method of Compound 271, the corresponding final product compounds were obtained by performing four-step reactions with the starting materials in the following table.

[0639]

[0640] Referring to the methods of Steps 3 and 4 in the synthesis method of Compound 271, the corresponding final product compounds were obtained by performing two-step reactions with the starting materials in the following table.

[0641]

[0642] The synthesis method of 292-A involved in the above table is

[0643]

[0644] Referring to the method in Step 2 of Example 5-b, using 292-B (500 mg, 2.54 mmol) as the raw material, reacting with 271-D (517.7 mg, 2.54 mmol) to obtain the white solid compound 292-A (70 mg, yield 7.2%). LC-MS (ESI) m / z: 384.4 (M+H) + 。

[0645] Synthesis of Compound 274 in Example 52

[0646]

[0647] Step 1: To a solution of Compound 274-A (5 g, 32.4 mmol) in toluene (50 mL), add 274-B (6.04 g, 32.4 mmol) and paraformaldehyde (1.95 g, 64.8 mmol, 2 eq), stir and react at 50 °C for 16 hours. Concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (EA:PE, EA from 0 to 30%) to obtain the white solid compound 274-C (9 g, yield 79%). LC-MS: (ESI) m / z [M+H] + 353.2。

[0648] Step 2: To a solution of Compound 274-C (6.5 g, 18.4 mmol) in DCM (60 mL), add MnO2 (16 g, 184 mmol, 10 eq), stir and react at 25 °C for 5 hours. Filter, concentrate under reduced pressure to obtain the white solid compound 274-D (2 g), and directly use the crude product for the next step reaction. LC-MS: (ESI) m / z [M+H] + 351.1。

[0649] Step 3: Referring to the method in Step 1 of Example 2, using Compound 274-D (2 g) for reaction to obtain the yellow oily compound 274-E (2 g, two-step yield about 28%). LC-MS: (ESI) m / z [M+H] + 391.2。

[0650] Step 4: Referring to the method in Step 2 of Example 39 (representative method for deprotecting Boc group), using Compound 274-E (2.5 g) for reaction to obtain the yellow oily compound 274-F (1.8 g), and directly use the crude product for the next step reaction. LC-MS: (ESI) m / z [M+H] + 291.1。

[0651] Step 5: Referring to the method in Step 1 of Example 51, react with 274-E (500 mg, 1.24 mmol, TFA salt) to obtain the yellow oily compound 274-G (230 mg, with an overall yield of about 34% in two steps). LC-MS: (ESI) m / z [M+H] + 381.1。

[0652] Steps 6 and 7: Referring to the methods in Steps 2 and 3 of Example 2, perform two-step reactions with 274-G (143 mg, 603 μmol) to obtain the white solid compound 274 (1 mg, with an overall yield of about 1.4% in two steps). 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 6.89 (s, 1H), 6.73 - 6.85 (m, 1H), 6.46 - 6.53 (m, 1H), 6.05 - 6.15 (m, 1H), 5.73 - 5.78 (m, 1H), 5.63 - 5.71 (m, 1H), 5.36 - 5.43 (m, 1H), 3.73 - 3.80 (m, 3H), 3.48 - 3.61 (m, 6H), 2.41 (brs, 4H), 2.12 - 2.26 (m, 2H), 1.29 (td, J = 4.4, 8.3 Hz, 1H), 0.93 - 1.12 (m, 1H), 0.63 - 0.70 (m, 1H). LC-MS: (ESI) m / z [M+H] + 373.3。

[0653] Synthesis of Compound 276 in Example 53

[0654]

[0655] To a solution of compound 14 (100 mg, 427 μmol) in DCM (5 mL), add m-CPBA (4.33 mg, 21.3 μmol, 85% purity, 0.05 eq). After stirring at 25 °C for 15 minutes, add NBS (76 mg, 427 μmol) and react at 40 °C for 16 hours. After completion of the reaction, concentrate the solvent under reduced pressure and purify by silica gel column chromatography (EA:PE, EA from 0 to 6%) to obtain the white solid compound 276 (100 mg, yield 75%). 11H NMR (400 MHz, DMSO-d6) δ (ppm) 9.13 - 9.45 (m, 1H), 6.94 - 7.12 (m, 1H), 5.84 (d, J = 4.8 Hz, 0.22H), 5.47 (s, 0.75H), 3.69 - 3.85 (m, 3H), 2.56 - 2.63 (m, 0.27H), 2.26 - 2.37 (m, 1.61H), 2.17 - 2.21 (m, 3H), 1.07 - 1.37 (m, 1H), 0.78 - 1.06 (m, 1H). LC-MS: (ESI) m / z. [M+H] + 313.0.

[0656] Synthesis of Compound 277 in Example 54

[0657]

[0658] Step 1: To a mixture of Compound 14-a (800 mg, 2.77 mmol) and 277-B (900 mg, 3.58 mmol) in toluene (15 mL) and H2O (5 mL), cesium carbonate (2.7 g, 8.3 mmol) was added. After thoroughly displacing nitrogen, RuPhosPd G3 catalyst (CAS: 1445085-77-7, 231 mg, 276 μmol) was added, and the mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and the mixture was extracted with EA (10 mL × 3). After conventional post-treatment operations, a residue was obtained, and the residue was purified by silica gel column chromatography (EA:PE, EA from 0 to 20%) to obtain white solid Compound 277-C (960 mg, yield 98%). LC-MS: Rt = 0.983 min, (ESI) m / z [M+H] + 354.2

[0659] Step 2: Compound 277-C (870 mg, 2.46 mmol) was stirred in a dioxane solution of HCl (2 M, 10 mL) at 20 °C for 2 hours. The mixture was concentrated under reduced pressure to obtain green solid Compound 277-D (570 mg, HCl salt), and the crude product was directly used in the next step. LC-MS: (ESI) m / z [M+H] + 196.1。

[0660] Step 3: Referring to the method of Step 2 in Example 5-b, using 277-D (570 mg, HCl salt) as the raw material, it was reacted with 1-adamantaneacetic acid (956 mg, 2 eq) to obtain white solid Compound 277-E (1.0 g, two-step yield approximately 74%). LC-MS: (ESI) m / z [M+H] + 548.4。

[0661] Step 4: Referring to the method of Example 34, using 277-E (1.0 g) as the raw material for reaction. After the reaction, concentrate under reduced pressure, adjust the pH to 1 with 1M HCl. After the solid precipitates, filter to obtain the white solid compound 277-F (700 mg). The crude product is directly used for the next reaction. LC-MS: (ESI) m / z [M+H] + 372.2

[0662] Steps 5 to 7: Referring to the method of Example 2, using 277-F (645 mg) as the raw material for three-step reaction to obtain the white solid compound 277 (17 mg, the overall yield of four steps is 12.6%). LC-MS: (ESI) m / z [M+H] + 440.2 1 HNMR (400 MHz, DMSO-d6) δ (ppm) 9.48 - 9.88 (m, 1H), 7.60 - 7.79 (m, 1H), 6.78 - 6.98 (m, 1H), 6.45 - 6.56 (m, 1H), 5.72 (d, J = 4.6 Hz, 0.2H), 5.37 (s, 0.8H), 3.64 - 3.81 (m, 3H), 3.10 - 3.23 (m, 2H), 2.58 (br t, J = 7.4 Hz, 2H), 2.21 (m, 1.8H), 1.89 (br s, 3H), 1.73 - 1.83 (m, 2H), 1.44 - 1.71 (m, 13H), 1.24 - 1.35 (m, 1H), 0.92 - 1.09 (m, 1H), 0.71 - 0.78 (m, 0.2H)

[0663] The synthesis method of compound 14-a is as follows:

[0664]

[0665] Step 1: Add chloromethyl ethyl ether (1.96 g, 20.74 mmol) and K2CO3 (8.60 g, 62.21 mmol) to a solution of 5-bromo-2,4-dihydroxybenzene-1-carbaldehyde (4.5 g, 20.74 mmol) in acetone (100 mL). React at 20 °C for 16 hours. Add saturated NH4Cl aqueous solution (50 mL), and extract with EA (50 mL x 3). After the conventional post-treatment operation 2, the crude product is obtained. The crude product is purified by silica gel column chromatography (EA:PE, EA from 0 to 9%) to obtain the white solid 5-bromo-4-[(ethoxymethyl)oxy]-2-hydroxybenzene-1-carbaldehyde (3.22 g, yield 56%).

[0666] Step 2: Add methyl iodide (2.23 g, 15.70 mmol) and K2CO3 (3.62 g, 26.17 mmol) to a mixture of 5-bromo-4-[(ethoxymethyl)oxy]-2-hydroxybenzene-1-carbaldehyde (3.6 g, 13.09 mmol) in DMF (2 mL). React at 20 °C for 16 h. Add water (50 mL), and extract with EA (50 mL x 2). After conventional post-treatment operation 2, a crude product is obtained. The crude product is purified by silica gel thin layer chromatography (EA:PE, EA from 6 to 9%) to obtain white solid 14-a (3.58 g, yield 94%).

[0667] Synthesis of Compound 129 in Example 55

[0668]

[0669] Step 1: Place Wang Resin (Wang Resin, 400 mg, 0.544 mmol) in a 40 mL reaction flask and suspend it in 10 mL of DCM / DMF (1:9). Dissolve a solution of Compound 129-A (440 mg, 1.07 mmol) and HOBt (146 mg, 1.08 mmol) in DMF (1 mL) in a separate vial, and add the solution to the resin. Add DMAP (8 mg, 65.5 μmol) to the reaction flask, then add DIC (145 mg, 1.15 mmol), and shake the reaction mixture at 25 °C for 6 h. Add acetic anhydride (120 mg, 1.17 mmol) and pyridine (108 mg, 1.36 mmol) to the reaction flask, and shake for another 30 minutes at 25 °C to cap the unreacted hydroxyl groups on the resin. Filter the resin and wash it twice with 20 mL of DMF and 5 times with 20 mL of DCM to obtain wet resin 129-B for the next step.

[0670] Step 2: Place resin 129-B (0.544 mmol) in a solid-phase synthesis reactor and add 15 mL of DMF. After stirring for 30 seconds to swell, remove the solvent by vacuum filtration. Add 15 mL of 20% piperidine / DMF, stir for 15 minutes, and then remove the solvent by vacuum filtration. Add 15 mL of 20% piperidine / DMF again, stir for 15 minutes, and then remove the solvent by vacuum filtration and wash the resin four times with 15 mL of DMF. Dissolve 2-cyclohexylacetic acid (315 mg, 2.22 mmol), HATU (833 mg, 2.19 mmol), and HOAt (301 mg, 2.21 mmol) in DMF (15 mL) and add the solution to the resin, stirring for 30 seconds. Add DIPEA (643 mg, 4.98 mmol). Stir the reaction mixture at 25 °C for 2 hours, then remove the solvent by vacuum filtration and wash the resin four times with 15 mL of DMF. Collect the resulting resin 129-C after washing it four times with 15 mL of DCM into a reaction flask for the next reaction.

[0671] Transfer some resin beads into a small glass tube, add 1 mL of a DCM solution of 5% TFA and wait for 3 hours. Remove the solvent and dilute with ACN / water (1:1, 1 mL), filter, and monitor the reaction by LCMS to obtain the target compound. LC-MS: (ESI) m / z. [M+H] + 313.1.

[0672] Step 3: Place resin 129-C (544 μmol) in a reaction flask, add DCM (10 mL) and phenylsilane (482 mg, 4.46 mmol), stir gently for 1 minute, and let it stand for 15 minutes to swell the resin. Degas the reaction suspension under vacuum and purge it with nitrogen five times. Add Pd(PPh3)4 (150 mg, 130 μmol) to the reaction suspension, degas under vacuum and purge with nitrogen five times, then shake the reaction suspension under a nitrogen atmosphere at 25 °C for 1.5 hours. Filter to obtain the resin and wash the resin five times with 15 mL of DMF. Add a DMF solution (10 mL) of 0.5% PIX (isopropylxanthate potassium salt) and 0.5% DIEA, stir gently for 5 minutes, then remove the solvent by vacuum filtration, repeat 2 times, and then wash the resin five times with 15 mL of DMF. Wash the resin five times with 15 mL of DCM again to obtain an off-white resin 129-D for the next reaction.

[0673] Step 4: Place resin 129-D (544 μmol) in a reaction flask. Add 5% TFA / DCM solution (15 mL) to the resin and shake at 25 °C for 4 hours. Filter the reaction suspension and wash the resin three times with 15 mL of DCM. Combine the filtrates and concentrate under reduced pressure. Dissolve the obtained crude product in 5 mL of deionized water and filter to remove insoluble substances. Repeat this process 3 times. After combining the filtrates and freeze-drying, a colorless syrup-like product 129-E (156 mg, yield 83.77%, TFA salt) is obtained and used directly for the next step. LC-MS: (ESI) m / z. [M+H] + 229.1;

[0674] Step 5: Add TEA (51 mg, 503 μmol) to a DMF (1.5 mL) solution of 129-E (62 mg, 181 μmol, 1.2 eq., TFA salt), and then add compound 112 (40 mg, 153 μmol, 1.0 eq). Stir the reaction mixture at 55 °C for 12 hours. Concentrate the reaction mixture under reduced pressure and purify by prep HPLC (FA method - A; B%: 25% - 45%, 10 min) to obtain a off-white solid compound 129 (32 mg, 41.5% yield). LC-MS: (ESI) m / z. [M+H]+ 491.4; 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.36 - 7.55 (m, 2H), 6.93 (s, 1H), 6.46 (s, 1H), 5.61 - 5.69 (m, 1H), 4.42 (br s, 1H), 3.74 (s, 3H), 3.43 - 3.70 (m, 2H), 2.66 - 2.90 (m, 2H), 2.38 - 2.66 (m, 5H), 1.97 - 2.22 (m, 3H), 1.53 - 1.76 (m, 6H), 0.99 - 1.28 (m, 3H), 0.82 - 0.99 (m, 2H).

[0675] Referring to the method of Example 55, use the starting materials in the following table to replace compound 129-A in the first step and perform a five-step reaction to obtain the corresponding final product compound.

[0676]

[0677] Synthesis of Compound 125 in Example 56

[0678]

[0679] Step 1: Dissolve compound 125-A (780 mg, 1.95 mmol) in DCM (15 mL), and add DIPEA (964.57 mg, 7.46 mmol) to the solution. Add 2-chlorotrityl chloride resin (CTC resin) (1.3 g, 1.0 mmol / g, 1.30 mmol) to the solution, and shake the mixture at 25 °C for 2 hours. Add 2 mL of methanol to the solution, and shake the mixture at 25 °C for 30 minutes. Filter the mixture, wash the resin five times with 20 mL of DCM, and dry it under vacuum to obtain the desired yellow solid resin 125-B (1.78 g).

[0680] Step 2: Place resin 125-B (1.54 g, 1.0 mmol) in a solid-phase synthesis reactor, add 20 mL of DCM to soak the resin for 15 minutes to swell the resin, then filter it under vacuum to remove the solvent, and wash it once with 20 mL of DMF. Add 20 mL of 20% piperidine / DMF, stir for 30 minutes, and then remove the solvent by vacuum filtration. Add 20 mL of 20% piperidine / DMF again, stir for 30 minutes, and then remove the solvent by vacuum filtration and wash the resin five times with 20 mL of DMF. Dissolve compound 129-A (827 mg, 2.02 mmol), HATU (768 mg, 2.02 mmol), and HOAt (275 mg, 2.02 mmol) in DMF (10 mL) and add the solution to the resin, and stir for 30 seconds. Add DIPEA (890 mg, 6.89 mmol). Stir the reaction mixture at 25 °C for 2 hours, then remove the solvent by vacuum filtration and wash the resin five times with 15 mL of DMF. Wash the obtained resin 125-C five times with 15 mL of DCM for the next step.

[0681] Step 3: Place resin 125-C (0.75 g, ~0.5 mmol) in a solid-phase synthesis reactor. Add 15 mL of DCM and soak for 15 minutes to swell the resin, then filter under vacuum to remove the solvent, and wash once with 20 mL of DMF. Add 10 mL of 20% piperidine / DMF, stir for 15 minutes, and then remove the solvent by vacuum filtration. Add 20 mL of 20% piperidine / DMF again, stir for 15 minutes, and then remove the solvent by vacuum filtration and wash the resin five times with 15 mL of DMF. Dissolve 2-cyclohexylacetic acid (285 mg, 2.00 mmol), HATU (760 mg, 2.00 mmol), and HOAt (273 mg, 2.01 mmol) in DMF (10 mL) and add the solution to the resin, stirring for 30 seconds. Add DIPEA (649 mg, 5.02 mmol). The reaction mixture is stirred at 25 °C for 2 hours, then the solvent is removed by vacuum filtration and the resin is washed five times with 15 mL of DMF. The resulting resin 125-D is washed five times with 15 mL of DCM and then collected in a reaction flask for the next step.

[0682] Step 4: Referring to the method of Step 3 in Example 55, react with resin 125-D (0.5 mmol, 1.0 eq.) to obtain yellow resin 125-E for the next reaction.

[0683] Transfer some resin beads to a small glass tube, add 1 mL of a DCM solution of 2% TFA and wait for 15 minutes. Remove the solvent and dilute with acetonitrile / water (1:1, 1 mL), filter, and monitor the reaction by LCMS to obtain the target compound. LC-MS: (ESI) m / z. [M+H] + 388.2;

[0684] Step 5: Referring to the method of Step 4 in Example 55, react with resin 125-E (0.5 mmol, 1.0 eq.) to obtain off-white solid 125-F (232 mg, 92.52% yield, TFA salt). LC-MS: (ESI) m / z [M+H] + 388.3;

[0685] Step 6: Referring to the method of Step 5 in Example 55 (reaction temperature is 25 °C), react with 125-F (71 mg, 183 μmol, TFA salt) to obtain white solid compound 125 (72 mg, 69.07% yield). LC-MS: (ESI) m / z. [M+H] + 650.6; 11H NMR (400 MHz, CDCl3) δ (ppm) 7.03 - 7.21 (m, 3H), 6.89 - 7.01 (m, 1H), 6.47 (s, 1H), 5.62 - 5.69 (m, 1H), 4.59 - 4.74 (m, 1H), 3.77 (s, 3H), 3.70 - 3.86 (m, 2H), 3.41 - 3.67 (m, 9H), 3.23 - 3.39 (m, 1H), 2.73 - 2.94 (m, 2H), 2.48 - 2.70 (m, 7H), 1.98 - 2.22 (m, 3H), 1.55 - 1.83 (m, 6H), 1.05 - 1.33 (m, 3H), 0.77 - 1.02 (m, 2H).

[0686] Referring to the method of Example 56, the starting materials in the following table were used to replace compounds 129-A and 125-B in the second step to carry out a five-step reaction to obtain the corresponding final product compounds.

[0687]

[0688] Synthesis of Compound 128 in Example 57

[0689]

[0690] Step 1: Place resin 129-B (0.544 mmol) in a reaction flask, add DCM (10 mL) and phenylsilane (482 mg, 4.46 mmol), stir gently for 1 minute, and let the resin swell for 15 minutes. Degas the reaction suspension under vacuum and purge with nitrogen five times. Add Pd(PPh3)4 (140 mg, 121 μmol) to the reaction suspension, degas under vacuum and purge with nitrogen five times, and then shake the reaction suspension under a nitrogen atmosphere for 1.5 hours. Filter to obtain the resin and wash the resin five times with 15 mL of DCM and three times with 15 mL of DMF to obtain yellow resin 128-A for the next step.

[0691] Step 2: Place resin 128-A (0.544 mmol) in a solid-phase synthesis reactor and wash it once with 20 mL of DMF. Dissolve 2-cyclohexylacetic acid (315 mg, 2.22 mmol), HATU (834 mg, 2.19 mmol), and HOAt (302 mg, 2.22 mmol) in DMF (10 mL) and add the solution to the resin, stirring for 30 seconds. Add DIPEA (649 mg, 5.02 mmol). The reaction mixture is stirred at 25 °C for 2 hours, then the solvent is removed by vacuum filtration and the resin is washed twice with 15 mL of DMF. Add a DMF solution (10 mL) of 0.5% PIX and 0.5% DIPEA, stir for 5 minutes, then remove the solvent by vacuum filtration. After repeating this 2 times, wash the resin three times with 15 mL of DMF. Add 15 mL of 20% piperidine / DMF, stir for 30 minutes, then remove the solvent by vacuum filtration. Add 15 mL of 20% piperidine / DMF again, stir for 30 minutes, then remove the solvent by vacuum filtration and wash the resin four times with 15 mL of DMF.

[0692] Steps 3 and 4: Referring to the methods of Step 4 and Step 5 of Example 55, perform two-step reactions with 128-B to obtain white solid compound 128, with a two-step yield of 36%. LCMS: (ESI) m / z = 491.5 (M+1) + ; 1 H NMR (400 MHz, CDCl3) δ 7.51 - 7.68 (m, 1H), 6.88 - 7.11 (m, 1H), 6.96 (s, 1H), 6.46 (s, 1H), 5.61 - 5.72 (m, 1H), 4.50 (br s, 1H), 3.74 (s, 3H), 3.42 - 3.68 (m, 2H), 2.69 - 2.96 (m, 2H), 2.41 - 2.69 (m, 5H), 2.07 - 2.24 (m, 1H), 1.92 - 2.07 (m, 2H), 1.53 - 1.76 (m, 6H), 1.00 - 1.28 (m, 3H), 0.77 - 0.97 (m, 2H).

[0693] Referring to the method of Example 57, use the starting materials in the following table to replace compound 129-A in the first step to perform five-step reactions to obtain the corresponding final compounds.

[0694]

[0695] Synthesis of Compound 126 in Example 58

[0696]

[0697] Step 1: Resin 125-C (0.75 g, 0.5 mmol) was placed in a reaction flask, and DCM (15 mL) and phenylsilane (438 mg, 4.05 mmol) were added. The mixture was stirred gently for 1 minute and left for 15 minutes to allow the resin to swell. The reaction suspension was degassed under vacuum and purged with nitrogen five times. Pd(PPh3)4 (150 mg, 130 μmol) was added to the reaction suspension. After degassing under vacuum and purging with nitrogen five times, the reaction suspension was shaken under a nitrogen atmosphere for 1.5 hours. The resin was filtered and washed with 15 mL of DMF five times. The resulting resin was placed in a solid-phase synthesis reactor. 2-Cyclohexylacetic acid (285 mg, 2.00 mmol), HATU (761 mg, 2.00 mmol), and HOAt (273 mg, 2.01 mmol) were dissolved in DMF (15 mL), and the solution was added to the resin and stirred for 30 seconds. DIPEA (742 mg, 5.74 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours, then the solvent was removed by vacuum filtration and the resin was washed with 15 mL of DMF four times. 15 mL of 20% piperidine / DMF was added, stirred for 15 minutes, and then the solvent was removed by vacuum filtration. 15 mL of 20% piperidine / DMF was added again, stirred for 15 minutes, and then the solvent was removed by vacuum filtration and the resin was washed with 15 mL of DMF four times.

[0698] Steps 2 and 3: Referring to the method of Steps 4 and 5 in Example 55 (the reaction temperature in Step 5 was 25 °C), a two-step reaction was carried out with 126-A to obtain a white solid compound 126, with a two-step yield of 31%. LC-MS: (ESI) m / z [M+H] + 650.6; 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.64 - 7.78 (m, 1H), 7.13 - 7.27 (m, 1H), 6.97 (s, 1H), 6.70 - 6.88 (m, 1H), 6.47 (s, 1H), 5.57 - 5.79 (m, 1H), 4.60 - 4.72 (m, 1H), 3.76 (s, 3H), 3.70 - 3.84 (m, 2H), 3.43 - 3.67 (m, 10H), 3.23 - 3.37 (m, 1H), 3.23 - 3.37 (m, 1H), 2.47 - 2.93 (m, 9H), 2.09 - 2.22 (m, 1H), 1.90 - 2.09 (m, 2H), 1.55 - 1.79 (m, 6H), 1.04 - 1.31 (m, 3H), 0.78 - 0.99 (m, 2H).

[0699] Synthesis of Compound 122 in Example 59

[0700]

[0701] In Step 1, referring to the method in Step 2 of Example 56, react 122-B with 125-B instead of compound 129-A to obtain 122-A. Then, referring to the method of Example 58, use 122-A as the raw material to carry out three-step reactions to obtain the white solid compound 122. LC-MS: (ESI) m / z. [M+H] + 650.4; 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.57 - 7.79 (m, 1H), 7.10 - 7.27 (m, 1H), 6.97 (s, 1H), 6.60 - 6.78 (m, 1H), 6.47 (s, 1H), 5.55 - 5.75 (m, 1H), 4.62 - 4.73 (m, 1H), 3.77 (s, 3H), 3.69 - 3.87 (m, 2H), 3.38 - 3.69 (m, 9H), 3.19 - 3.37 (m, 1H), 2.72 - 2.97 (m, 2H), 2.35 - 2.72 (m, 7H), 2.08 - 2.22 (m, 1H), 1.88 - 2.08 (m, 2H), 1.47 - 1.80 (m, 6H), 1.04 - 1.33 (m, 3H), 0.80 - 0.98 (m, 2H)

[0702] Synthesis of Compound 286 in Example 60

[0703]

[0704] Step 1: Add acetic anhydride (2.03 g, 19.91 mmol) to a pyridine (10 mL) solution of compound 67-A (500 mg, 1.99 mmol). React at 25 °C for 16 hours. Concentrate under reduced pressure, add water (10 mL), and extract with EA (5 mL x 3). After conventional post-treatment operations, obtain the crude product, and purify the crude product by silica gel column chromatography (EA:PE, EA from 0 to 50%) to obtain a yellow solid (560 mg, yield 95.94%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H) 8.97 (d, J = 8.53 Hz, 1H) 8.10 (d, J = 8.03 Hz, 1H) 7.86 (s, 1H) 7.79 - 7.84 (m, 1H) 7.71 - 7.76 (m, 1H) 2.49 - 2.50 (m, 3H).

[0705] Steps 2 and 3: Referring to the methods of Steps 2 and 3 in Example 12, a two-step reaction was carried out using the above product (510 mg, 1.74 mmol) as the raw material to obtain a yellow solid compound 286, with a two-step yield of 73.6%. LCMS: m / z = 349.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ ppm 8.03 - 8.12 (m, 1H) 7.90 - 7.98 (m, 1H) 7.56 - 7.63 (m, 2H) 7.52 (s, 1H) 6.51 (dd, J = 10.57, 7.19 Hz, 1H) 2.87 - 2.94 (m, 2H) 2.67 - 2.77 (m, 1H) 2.59 - 2.67 (m, 1H) 2.47 - 2.51 (m, 3H).

[0706] Chiral resolution of compound 172 in Example 61

[0707] Compound 172 (30 mg) was subjected to chiral resolution by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO2 - EtOH (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) to obtain compounds 293, 294, 295, and 296. Compound 293: (3 mg), white solid, SFC: Rt = 1.343 min. Compound 294: (10 mg), white solid, SFC: Rt = 1.497 min. Compound 295: (8 mg), white solid, SFC: Rt = 1.703 min. Compound 296: (3 mg), white solid, SFC: Rt = 1.775 min. The SFC analysis method was: column: ChiralpakAD - 3 100×4.6 mm I.D., 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); gradient: B from 5% to 40% within 3 minutes, 40% of B was held for 0.5 min, then 5% of B was held for 1.5 min; flow rate: 2.8 mL / min; column temperature: 35 °C; ABPR: 1500 psi.

[0708] Biological activity test example 1

[0709] The inhibitory effect of the compound on the binding of TDG and double-stranded DNA substrates was evaluated using the HTRF (homogeneous time-resolved fluorescence) technique.

[0710] Reagents and consumables

[0711]

[0712] Instrument

[0713] Microplate reader (manufacturer: Perkin Elmer, model: Envision multimode microplate reader, equipped with HTRF functional module) and Echo 550 (manufacturer: Labcyte, model: Echo 550)

[0714] Experimental method

[0715] 1. Preparation of compound concentration gradient: The starting concentration of the test compound is 250 μM, diluted 3-fold, with 10 concentrations, and duplicate wells are detected. Dilute it into 10 different concentrations of solutions with a 40-fold final concentration in a 384-well plate. Then transfer 500 nl to a 384-well reaction plate using Echo 550 for standby. Add 500 nl of 100% DMSO or dsDNA substrate without Biotin labeling to the negative control well and positive control well respectively.

[0716] 2. Add 1.5 μl / well of Epigeneous Binding Domain diluent buffer to the 384-well plate and centrifuge at 1000 rpm for 1 min.

[0717] 3. Add 4 μl of 5-fold final concentration of His-tagged TDG protein (final concentration 40 nM, diluted with Epigeneous Binding Domain diluent buffer) to the 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 10 min.

[0718] 4. Add 4 μl of 5-fold final concentration of Biotin-labeled dsDNA substrate (final concentration 40 nM, diluted with Epigeneous Binding Domain diluent buffer) to the 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 30 min.

[0719] 5. Add 5 μl of 4-fold final concentration of Streptavidin-XL665 (final concentration 5 nM, diluted with Epigeneous Binding Domain Detection buffer) to the 384-well plate and centrifuge at 1000 rpm for 1 min.

[0720] 6. Add 5 μl of 4-fold final concentration of MAb Anti-6HIS-Eu cryptate Gold (final concentration 0.1 μg / ml, diluted with Epigeneous Binding Domain Detection buffer) to the 384-well plate and centrifuge at 1000 rpm for 1 min.

[0721] Incubate overnight at 4°C and read HTRF with a microplate reader.

[0722] Data analysis

[0723] 1. Calculate the Ratio value for each well

[0724] Ratio = Signal 665nm / Signal 620nm × 104

[0725] 2. Calculate the delta Ratio value for each well

[0726] delta Ratio = Ratio standard or sample - Ratio standard 0 (negative control)

[0727] 3. Use four - parameter logistic (4PL) curve fitting for IC 50

[0728] The biological test results are recorded in the following table. The results show that the example compounds of the present invention have a strong inhibitory effect on the binding of TDG and double - stranded DNA substrates.

[0729] A: IC 50 ≤500 nM;

[0730] B: 500 nM < IC 50 ≤5 μM;

[0731] C: 5 μM < IC 50 ≤50 μM;

[0732] D: >50 μM

[0733] Using the above - mentioned test method, the effects of the following compounds were obtained:

[0734]

[0735]

[0736] Inhibitory effect of compound 14 in biological activity test example 2 on the proliferation of TP53 mutant and wild - type tumor cells

[0737] Inhibitory effect of compound 14 on the proliferation of TP53 mutant and wild - type tumor cells, IC 50 , and both the TP53 mutant and wild - type tumor cells used in this example are human tumor cells.

[0738] Tumor cells were plated on 384-well plates and treated with DMSO or compound 14 at the specified concentrations (0.04–30 μM). After 6 days of incubation, the chemiluminescence intensity was measured using the CellTiter-Glo luminescence assay kit (Promega). The curves were fitted using GraphPad Prism software, and the IC 50 value was calculated.

[0739] Results showed that compound 14 had a certain inhibitory effect on various tumor cell lines, including lung cancer, liver cancer, skin cancer, bladder cancer, breast cancer, colon cancer, and esophageal cancer cells. In particular, it had a significant inhibitory effect on the in vitro proliferation of p53 mutant tumor cell lines (including NCI-H446, Calu-1, NCI-H1299, RERF-LC-AI, NCI-H211, NCI-H2009, NCI-H23, VMRC-LCP, NCI-H441, PC9, NCI-H520, EBC-1, NCI-H1975, NCI-H2342, NCI-H647, HCC95, SK-LU-1, SW-900, SNU423, SNU449, HuCCT1, PLC / PRF / 5, SNU387, Hep3B, JHH-2, JHH7, SNU761, Huh7, CHL-1, RPMI-7951, SK-MEL-2, SK-MEL-28, MeWo, SK-MEL-3, 5637, UMUC3, RT112, HT1376, BT549, MDA-MB-468, MDA-MB-231, HS578T, EFM-19, MDA-MB-436, Colo320DM, Colo205, RKO E6, NCI-H508, TE-15, TE-8, TE-1, TE-9, TE-10, TE-4, TE-6, TE-14, T.T). Figure 1 ) This indicates that each compound of the present invention, including compound 14, has excellent anti-tumor activity, especially against p53 mutant tumor cells.

[0740] All documents mentioned in the present invention are incorporated herein by reference as if each individual document was specifically and individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound as shown in Formula 1, or a deuterated product, stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof: R1 is selected from the following group: OH, H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 3-12 membered heterocycle, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-3-12 membered heterocycle, substituted or unsubstituted -C1-C6 alkyl-phenyl, substituted or unsubstituted -O-phenyl, substituted or unsubstituted C1-C4 alkyl-C(O)-, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C6 alkyl-NH-, (substituted or unsubstituted C1-C6 alkyl)2-N-, -O(CH2) s R 10 , or -S(CH2) s R 10 ; s is 0, 1, 2 or 3; R 10 Selected from the group consisting of H, substituted or unsubstituted C 3-8 Carbocyclic ring, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring; R2 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6 alkyl; R3 is selected from the following group: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 12 Cycloalkyl, or (C1-C6 alkyl)C(O)R8, (C1-C6 alkyl)C(O)NHR8, (C1-C6 alkyl)C(O)N(substituted or unsubstituted C1-C6 alkyl)R8, (C1-C6 alkyl)NHC(O)R8, (C1-C6 alkyl)C(O)OR8; The R8 is selected from the following groups: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 Aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, adamantane, or a substituted or unsubstituted group selected from the group consisting of: -(CH2) m NHC(O)(CH2) n R 13 、-(CH2)CHR9NHC(O)(CH2) n R 13 、CHR9(CH2)NHC(O)(CH2) n R 13 ; The R9 is selected from the following group: H, -COOH, -CONHR 12 、-CONHCH2R 12 、-CONH(CH2CH2O) m (CH2) n COOH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 A carbocyclic ring, a substituted or unsubstituted 3-12-membered heterocyclic ring, or a substituted or unsubstituted 5-12-membered heteroaromatic ring; R 12 Selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring; The R 13 Selected from the group consisting of substituted or unsubstituted C3-C 10 A carbocyclic ring, a substituted or unsubstituted 5-12 membered heterocyclic ring; m and n are each independently 0, 1, 2 or 3; R4 is selected from the following group: H, halogen, cyano, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 amine, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12-membered heterocyclic ring, substituted or unsubstituted 5-12-membered heteroaromatic ring, substituted or unsubstituted -O-5-12-membered heteroaromatic ring; Alternatively, R3 and R4 and the carbon atoms connected thereto together form a structure selected from the group consisting of a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; R5 and R6 are each independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C3-C8 carbocycle, or substituted or unsubstituted 3-10 membered heterocycle; or said R5 and R6 and the carbon atoms connected thereto together form a substituted or unsubstituted 3-12 membered carbocycle; R6' is selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl; X is selected from O or S; Z is selected from O, S or NR 14 ; Among them, R 14 is H or C1-C4 alkyl; R7 is selected from the following group: H, or C(O)R 11 、C(O)OR 11 、-CH2OC(O)OR 11 、-S(O)2NHR 11 ; The R 11 Selected from the group consisting of H, substituted or unsubstituted C1-C 16 Alkyl, substituted or unsubstituted C6-C 10 Aryl, -(OCH2CH2) m - substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-8 membered heterocyclic group; Unless otherwise specified, in the above formulas, the heteroaromatic ring, heteroaryl group, heterocycle or heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, S or O; the aromatic ring, aryl group, heteroaromatic ring or heteroaryl group may be a monocyclic ring or a condensed ring; the carbocyclic ring, cycloalkyl group, heterocyclic ring or heterocyclic group may be a monocyclic ring, a fused ring, a bridged ring or a spirocyclic ring; the carbocyclic ring, heterocyclic ring or heterocyclic group may be saturated or partially unsaturated, but not aromatic. The substitution refers to the substitution of the hydrogen atoms on the corresponding group by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C2-C 12 Alkoxycarbonyl, C1-C6 aldehyde, (C1-C6 alkyl)3Si, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, adamantane, C1-C6 alkyl-amino, C1-C 12 Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 acyl, unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or substituted C1-C4 alkyl-OC(O)NH-, unsubstituted or halogenated C1-C4 alkyl-SO-, a 5-7 membered heterocycle which is unsubstituted or substituted by C1-C4 alkyl, or phenyl (which may have 1-5 substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy).

2. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from the following groups: halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 3-12 membered heterocyclic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted -O-3-12 membered heterocyclic ring, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C6 alkyl-NH-, (substituted or unsubstituted C1-C6 alkyl)2-N-, or -O(CH2) s R 10 .

3. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula I has a structure shown in the following formula II: Wherein, the A ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the A ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered aromatic heterocycle.

4. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in the following formula IV: Wherein, the B ring is a substituted or unsubstituted C3-C8 carbocycle, or a substituted or unsubstituted 3-10 membered heterocycle; preferably, the B ring is a substituted or unsubstituted C3-C6 carbocycle, or a substituted or unsubstituted 3-8 membered heterocycle; wherein, the carbocycle or heterocycle may be saturated or partially unsaturated.

5. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in the following formula V: Wherein, the D ring is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted 5-10 membered aromatic heterocycle, a substituted or unsubstituted C3-C8 carbon ring, or a substituted or unsubstituted 3-10 membered heterocycle.

6. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in the following formula VI or VII: Wherein, Y is N or CH; Y1 and Y2 are each independently selected from the following group: CHR 15 NR 15 , O or S; t is 1 or 2; wherein R 15 Selected from the following group: deuterium, halogen, hydroxyl, carboxyl, thiol, amino, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.

7. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: R3 is selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted phenyl.

8. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: R5 and R6 are each independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl; or said R5 and R6 and the carbon atom connected thereto together form a substituted or unsubstituted 3-6 membered carbocyclic ring.

9. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: R3 is selected from the following group: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C 12 Cycloalkyl, or (C1-C6 alkyl)C(O)R8, (C1-C6 alkyl)C(O)NHR8, (C1-C6 alkyl)C(O)N(substituted or unsubstituted C1-C6 alkyl)R8, (C1-C6 alkyl)C(O)OR8; wherein R8 is selected from the following groups: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 Aryl, -(OCH2CH2) m -substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted group selected from the group consisting of: -(CH2) m NHC(O)(CH2) n R 13 、-(CH2)CHR9NHC(O)(CH2) n R 13 、CHR9(CH2)NHC(O)(CH2) n R 13 ; The R9 is selected from the following group: H, -COOH, -CONHR 12 、-CONHCH2R 12 、-CONH(CH2CH2O) m (CH2) n COOH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 R 12 Selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring; said R 13 Selected from the group consisting of substituted or unsubstituted C3-C 10 of carbon rings; m and n are each independently 0, 1, 2 or 3; R4 is selected from the following group: H, halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted -O-5-12 membered heteroaromatic ring; Alternatively, R3 and R4 and the carbon atom to which they are attached together form a substituted or unsubstituted C6-C10 aromatic ring, or a substituted or unsubstituted 5-10 membered aromatic heterocyclic ring.

10. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in the following formula III: Preferably, the compound has a structure as shown in the following formula III-A or III-B: Preferably, the compound has any structure selected from the following group:

11. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown in the following formula IX: Preferably, the compound has a structure as shown in the following formula IX-A or IX-B: Preferably, the compound has any structure selected from the following group:

12. The compound according to claim 1, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in the following formula X: Preferably, the compound has a structure as shown in the following formula XA or XB: Preferably, the compound has any structure selected from the following group:

13. The compound according to any one of claims 1 to 12, or a deuterated product, stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following group:

14. A pharmaceutical composition, characterized in that The invention comprises (i) the compound according to claim 1, or a deuterated product, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

15. Use of the compound according to any one of claims 1 to 13, or its deuterated product, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that: Used for preparing a drug for treating and / or preventing a disease associated with abnormal TDG expression; preferably, the disease is selected from the following group: In another preferred embodiment, the tumor is selected from the following group: lung cancer, acute leukemia, chronic leukemia, colorectal cancer, breast cancer, thyroid tumor, lymphoma, bile duct cancer, liver cancer, pancreatic cancer, bronchial cancer, esophageal cancer, skin cancer, bladder cancer, oral cancer, gastric cancer, genitourinary tract tumors, central and peripheral nervous system tumors, or a combination thereof; more preferably, the tumor is selected from the following group: melanoma, acute myeloid leukemia, small cell lung cancer, non-small cell lung cancer.

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